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Matsunami, Hiroaki

Overview:

We are interested in the molecular mechanisms underlying chemosensation (taste and smell) in mammals. The receptors that detect odorants, pheromones, and many tastants including bitter and sweet chemicals are G-protein coupled receptors (GPCRs), which typically have seven transmembrane domains. There are many important questions that are still unanswered in chemosensory neurobiology. How do tens of thousands of different chemicals (tastants, odorants, or pheromones) interact with more than one thousand chemosensory receptors (about 1000 odorant receptors, 40 taste receptors and 200 vomeronasal receptors in the case of mice or rats)? How is the information coded in sensory cells and in the brain? How does the brain direct appropriate behavioral responses? What are the mechanisms underlying development and regeneration of sensory cells and specific synapse connections? We address these questions using molecular biology, genome information and genetics.

The detection of tastants is mediated by taste receptor cells that are clustered in taste buds in the mouth. Interestingly, some people can taste certain chemicals, such as 6-n-propylthiouracil (a bitter compound) while others can't. Likewise, some strains of mice can taste certain bitter or sweet tastants while others can't. Based on these variations, the bitter and sweet taste loci have been mapped on human or mouse chromosomes. By using the increasingly powerful genome informatics tools, we as well as other groups, have identified families of GPCRs that may detect bitter and sweet compounds. We seek to understand how specific changes in nucleotide sequences cause these differences in taste sensitivity. Another goal is to understand how the gustatory system is organized.

In olfaction, the detection of volatile odorants is mediated by olfactory sensory neurons in the olfactory epithelium of the nose. Odorants are detected by about 1000 different types of odorant receptors that are encoded by a multigene family. Each olfactory sensory neuron expresses only one receptor type out of 1000 receptors. Axons of neurons expressing the same receptor all converge in a few glomeruli in the olfactory bulb of the brain. We wish to understand the mechanisms underlying this convergence.

Finally, we are interested in the pheromone sensing system. Pheromones are chemicals that are released from animals and induce innate behavior, such as mating or aggression, or hormonal changes in members of the same species.
The detection of pheromones is mediated primarily by a second olfactory sense organ, called the vomeronasal organ (VNO). We, as well as other groups, have found families of candidate pheromone receptors by comparing gene expression between single VNO neurons. Pheromone molecules may induce their effects by activating some of these receptors, which ultimately affect particular regions of the brain. We seek to understand how these pheromonal effects are mediated.

Positions:

Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor of Neurobiology

Neurobiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Education:

Ph.D. 1996

Ph.D. — Kyoto University (Japan)

News:

Grants:

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Basic predoctoral training in neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 1992
End Date
June 30, 2018

Training in Fundamental &Translational Neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 2005
End Date
February 29, 2016
Show More

Awards:

AAAS Fellows. American Association for the Advancement of Science, The.

Type
National
Awarded By
American Association for the Advancement of Science, The
Date
January 01, 2012

Publications:

Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice.

Each of the olfactory sensory neurons (OSNs) chooses to express a single G protein-coupled olfactory receptor (OR) from a pool of hundreds. Here, we show the receptor transporting protein (RTP) family members play a dual role in both normal OR trafficking and determining OR gene choice probabilities. Rtp1 and Rtp2 double knockout mice (RTP1,2DKO) show OR trafficking defects and decreased OSN activation. Surprisingly, we discovered a small subset of the ORs are expressed in larger numbers of OSNs despite the presence of fewer total OSNs in RTP1,2DKO. Unlike typical ORs, some overrepresented ORs show robust cell surface expression in heterologous cells without the co-expression of RTPs. We present a model in which developing OSNs exhibit unstable OR expression until they choose to express an OR that exits the ER or undergo cell death. Our study sheds light on the new link between OR protein trafficking and OR transcriptional regulation.

Authors
Sharma, R; Ishimaru, Y; Davison, I; Ikegami, K; Chien, M-S; You, H; Chi, Q; Kubota, M; Yohda, M; Ehlers, M; Matsunami, H
MLA Citation
Sharma, R, Ishimaru, Y, Davison, I, Ikegami, K, Chien, M-S, You, H, Chi, Q, Kubota, M, Yohda, M, Ehlers, M, and Matsunami, H. "Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice." eLife 6 (March 6, 2017).
PMID
28262096
Source
epmc
Published In
eLife
Volume
6
Publish Date
2017
DOI
10.7554/elife.21895

Examining the variable influence of population structure on odor perception

Authors
Trimmer, C; Willer, JR; Keller, A; Vosshall, LB; Katsanis, N; Matsunami, H; Mainland, J
MLA Citation
Trimmer, C, Willer, JR, Keller, A, Vosshall, LB, Katsanis, N, Matsunami, H, and Mainland, J. "Examining the variable influence of population structure on odor perception." CHEMICAL SENSES 41.9 (November 2016): E255-E255.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E255
End Page
E255

Molecular dynamics simulations reveal the ligand-dependent activation of hOR7D4

Authors
de March, CA; Bruguera, E; Topin, JJ; Matsunami, H; Golebiowski, J
MLA Citation
de March, CA, Bruguera, E, Topin, JJ, Matsunami, H, and Golebiowski, J. "Molecular dynamics simulations reveal the ligand-dependent activation of hOR7D4." CHEMICAL SENSES 41.9 (November 2016): E157-E157.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E157
End Page
E157

Receptor repertoire for aversive odorants

Authors
Hu, XS; Jiang, Y; Ikegami, K; Matsunami, H
MLA Citation
Hu, XS, Jiang, Y, Ikegami, K, and Matsunami, H. "Receptor repertoire for aversive odorants." CHEMICAL SENSES 41.9 (November 2016): E252-E252.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E252
End Page
E252

Synergistic control of olfactory receptor trafficking to the cell surface membrane in heterologous cells

Authors
Ikegami, K; Sharma, R; Bruguera, E; Yohda, M; Matsunami, H
MLA Citation
Ikegami, K, Sharma, R, Bruguera, E, Yohda, M, and Matsunami, H. "Synergistic control of olfactory receptor trafficking to the cell surface membrane in heterologous cells." CHEMICAL SENSES 41.9 (November 2016): E252-E252.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E252
End Page
E252

Improving the odorant sensitivity of olfactory receptor-expressing yeast with accessory proteins

Authors
Fukutani, Y; Tamaki, R; Ikegami, K; Matsunami, H; Yohda, M
MLA Citation
Fukutani, Y, Tamaki, R, Ikegami, K, Matsunami, H, and Yohda, M. "Improving the odorant sensitivity of olfactory receptor-expressing yeast with accessory proteins." CHEMICAL SENSES 41.9 (November 2016): E211-E211.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E211
End Page
E211

Olfactory receptor accessory proteins RTP1 and RTP2 play a crucial role in receptor gene choice, development and odor detection

Authors
Sharma, R; Ishimaru, Y; Davison, I; Ikegami, K; Matsunami, H
MLA Citation
Sharma, R, Ishimaru, Y, Davison, I, Ikegami, K, and Matsunami, H. "Olfactory receptor accessory proteins RTP1 and RTP2 play a crucial role in receptor gene choice, development and odor detection." CHEMICAL SENSES 41.9 (November 2016): E253-E253.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E253
End Page
E253

Vapor detection and discrimination with a panel of odorant receptors expressed in heterologous cells

Authors
Kida, H; Vihani, A; Mainland, J; Matsunami, H
MLA Citation
Kida, H, Vihani, A, Mainland, J, and Matsunami, H. "Vapor detection and discrimination with a panel of odorant receptors expressed in heterologous cells." CHEMICAL SENSES 41.9 (November 2016): E262-E263.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E262
End Page
E263

Mammalian odorant receptors: Heterologous expression and deorphanization

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Mammalian odorant receptors: Heterologous expression and deorphanization." CHEMICAL SENSES 41.9 (November 2016): E123-E123.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E123
End Page
E123

Effect of cytochrome P450 on the response of olfactory receptor

Authors
Asakawa, M; Fukutani, Y; Savangsuksa, A; Matsunami, H; Yohda, M
MLA Citation
Asakawa, M, Fukutani, Y, Savangsuksa, A, Matsunami, H, and Yohda, M. "Effect of cytochrome P450 on the response of olfactory receptor." CHEMICAL SENSES 41.9 (November 2016): E159-E159.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
9
Publish Date
2016
Start Page
E159
End Page
E159

Smelling Sulfur: Copper and Silver Regulate the Response of Human Odorant Receptor OR2T11 to Low Molecular Weight Thiols.

Mammalian survival depends on ultrasensitive olfactory detection of volatile sulfur compounds, since these compounds can signal the presence of rancid food, O2 depleted atmospheres, and predators (through carnivore excretions). Skunks exploit this sensitivity with their noxious spray. In commerce, natural and liquefied gas is odorized with t-BuSH and EtSH, respectively, as warnings. The hundred-million-fold difference in olfactory perception between structurally similar EtSH and EtOH has long puzzled those studying olfaction. Mammals detect thiols and other odorants using odorant receptors (ORs), members of the family of seven transmembrane G-protein-coupled receptors (GPCRs). Under-standing the regulator cofactors and response of ORs is particularly challenging due to the lack of X-ray structural models. Here, we combine computational modeling and site-directed mutagenesis with saturation transfer difference (STD) NMR spectroscopy and measurements of the receptor response profiles. We find that human thiol receptor OR2T11 responds specifically to gas odorants t-BuSH and EtSH, requiring ionic copper for its robust activation, and that this role of copper is mimicked by ionic and nanoparticulate silver. While copper is both an essential nutrient for life and, in excess, a hallmark of various pathologies and neurodegenerative diseases, its involvement in human olfaction has not been previously demonstrated. When screened against a series of alcohols, thiols, sulfides and metal-coordinating ligands, OR2T11 responds, with enhancement by copper, to the mouse semiochemical CH3SCH2SH and derivatives, to four-membered cyclic sulfide thietane and to one- to four-carbon straight-, branched-chain and five-carbon branched-chain thiols, but not to longer chain thiols, suggesting compact receptor dimensions. Alcohols are unreactive.

Authors
Li, S; Ahmed, L; Zhang, R; Pan, Y; Matsunami, H; Burger, JL; Block, E; Batista, VS; Zhuang, H
MLA Citation
Li, S, Ahmed, L, Zhang, R, Pan, Y, Matsunami, H, Burger, JL, Block, E, Batista, VS, and Zhuang, H. "Smelling Sulfur: Copper and Silver Regulate the Response of Human Odorant Receptor OR2T11 to Low Molecular Weight Thiols." Journal of the American Chemical Society (September 23, 2016).
PMID
27659093
Source
epmc
Published In
Journal of the American Chemical Society
Publish Date
2016

Refinement of Olfactory Receptor Transcribed Regions Improves the Accuracy of In Vivo Receptor Deorphanization

Authors
Ikegami, K; Jiang, Y; Chien, M-S; Yohda, M; Matsunami, H
MLA Citation
Ikegami, K, Jiang, Y, Chien, M-S, Yohda, M, and Matsunami, H. "Refinement of Olfactory Receptor Transcribed Regions Improves the Accuracy of In Vivo Receptor Deorphanization." September 2016.
Source
wos-lite
Published In
Chemical Senses
Volume
41
Issue
7
Publish Date
2016
Start Page
E83
End Page
E83

The human olfactory transcriptome.

Olfaction is a versatile sensory mechanism for detecting thousands of volatile odorants. Although molecular basis of odorant signaling is relatively well understood considerable gaps remain in the complete charting of all relevant gene products. To address this challenge, we applied RNAseq to four well-characterized human olfactory epithelial samples and compared the results to novel and published mouse olfactory epithelium as well as 16 human control tissues.We identified 194 non-olfactory receptor (OR) genes that are overexpressed in human olfactory tissues vs.The highest overexpression is seen for lipocalins and bactericidal/permeability-increasing (BPI)-fold proteins, which in other species include secreted odorant carriers. Mouse-human discordance in orthologous lipocalin expression suggests different mammalian evolutionary paths in this family. Of the overexpressed genes 36 have documented olfactory function while for 158 there is little or no previous such functional evidence. The latter group includes GPCRs, neuropeptides, solute carriers, transcription factors and biotransformation enzymes. Many of them may be indirectly implicated in sensory function, and ~70 % are over expressed also in mouse olfactory epithelium, corroborating their olfactory role. Nearly 90 % of the intact OR repertoire, and ~60 % of the OR pseudogenes are expressed in the olfactory epithelium, with the latter showing a 3-fold lower expression. ORs transcription levels show a 1000-fold inter-paralog variation, as well as significant inter-individual differences. We assembled 160 transcripts representing 100 intact OR genes. These include 1-4 short 5' non-coding exons with considerable alternative splicing and long last exons that contain the coding region and 3' untranslated region of highly variable length. Notably, we identified 10 ORs with an intact open reading frame but with seemingly non-functional transcripts, suggesting a yet unreported OR pseudogenization mechanism. Analysis of the OR upstream regions indicated an enrichment of the homeobox family transcription factor binding sites and a consensus localization of a specific transcription factor binding site subfamily (Olf/EBF).We provide an overview of expression levels of ORs and auxiliary genes in human olfactory epithelium. This forms a transcriptomic view of the entire OR repertoire, and reveals a large number of over-expressed uncharacterized human non-receptor genes, providing a platform for future discovery.

Authors
Olender, T; Keydar, I; Pinto, JM; Tatarskyy, P; Alkelai, A; Chien, M-S; Fishilevich, S; Restrepo, D; Matsunami, H; Gilad, Y; Lancet, D
MLA Citation
Olender, T, Keydar, I, Pinto, JM, Tatarskyy, P, Alkelai, A, Chien, M-S, Fishilevich, S, Restrepo, D, Matsunami, H, Gilad, Y, and Lancet, D. "The human olfactory transcriptome." BMC genomics 17.1 (August 11, 2016): 619-.
PMID
27515280
Source
epmc
Published In
BMC Genomics
Volume
17
Issue
1
Publish Date
2016
Start Page
619
DOI
10.1186/s12864-016-2960-3

Single cell transcriptome analysis of mouse carotid body glomus cells.

Carotid body (CB) glomus cells mediate acute oxygen sensing and the initiation of the hypoxic ventilatory response, yet the gene expression profile of these cells is not available. We demonstrate that the single cell RNA-Seq method is a powerful tool for identifying highly expressed genes in CB glomus cells. Our single cell RNA-Seq results characterized novel CB glomus cell genes, including members of the G protein-coupled receptor signalling pathway, ion channels and atypical mitochondrial electron transport chain subunits. A heterologous cell-based screening identified acetate (which is known to affect CB glomus cell activity) as an agonist for the most highly abundant G protein-coupled receptor (Olfr78) in CB glomus cells. These data established the first transcriptome profile of CB glomus cells, highlighting genes with potential implications in CB chemosensory function.The carotid body (CB) is a major arterial chemoreceptor containing glomus cells whose activities are regulated by changes in arterial blood content, including oxygen. Despite significant advancements in the characterization of their physiological properties, our understanding of the underlying molecular machinery and signalling pathway in CB glomus cells is still limited. To overcome this, we employed the single cell RNA-Seq method by performing next-generation sequencing on single glomus cell-derived cDNAs to eliminate contamination of genes derived from other cell types present in the CB. Using this method, we identified a set of genes abundantly expressed in glomus cells, which contained novel glomus cell-specific genes. Transcriptome and subsequent in situ hybridization and immunohistochemistry analyses identified abundant G protein-coupled receptor signalling pathway components and various types of ion channels, as well as members of the hypoxia-inducible factors pathway. A short-chain fatty acid olfactory receptor Olfr78, recently implicated in CB function, was the most abundant G protein-coupled receptor. Two atypical mitochondrial electron transport chain subunits (Ndufa4l2 and Cox4i2) were among the most specifically expressed genes in CB glomus cells, highlighting their potential roles in mitochondria-mediated oxygen sensing. The wealth of information provided by the present study offers a valuable foundation for identifying molecules functioning in the CB.

Authors
Zhou, T; Chien, M-S; Kaleem, S; Matsunami, H
MLA Citation
Zhou, T, Chien, M-S, Kaleem, S, and Matsunami, H. "Single cell transcriptome analysis of mouse carotid body glomus cells." The Journal of physiology 594.15 (August 2016): 4225-4251.
PMID
26940531
Source
epmc
Published In
The Journal of Physiology
Volume
594
Issue
15
Publish Date
2016
Start Page
4225
End Page
4251
DOI
10.1113/jp271936

Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism.

Mammals detect and discriminate numerous odors via a large family of G protein-coupled odorant receptors (ORs). However, little is known about the molecular and structural basis underlying OR response properties. Using site-directed mutagenesis and computational modeling, we studied ORs sharing high sequence homology but with different response properties. When tested in heterologous cells by diverse odorants, MOR256-3 responded broadly to many odorants, whereas MOR256-8 responded weakly to a few odorants. Out of 36 mutant MOR256-3 ORs, the majority altered the responses to different odorants in a similar manner and the overall response of an OR was positively correlated with its basal activity, an indication of ligand-independent receptor activation. Strikingly, a single mutation in MOR256-8 was sufficient to confer both high basal activity and broad responsiveness to this receptor. These results suggest that broad responsiveness of an OR is at least partially attributed to its activation likelihood.

Authors
Yu, Y; de March, CA; Ni, MJ; Adipietro, KA; Golebiowski, J; Matsunami, H; Ma, M
MLA Citation
Yu, Y, de March, CA, Ni, MJ, Adipietro, KA, Golebiowski, J, Matsunami, H, and Ma, M. "Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism." Proceedings of the National Academy of Sciences of the United States of America 112.48 (December 2015): 14966-14971.
PMID
26627247
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
48
Publish Date
2015
Start Page
14966
End Page
14971
DOI
10.1073/pnas.1517510112

Mammalian odorant receptors: functional evolution and variation.

In mammals, the perception of smell starts with the activation of odorant receptors (ORs) by volatile molecules in the environment. The mammalian OR repertoire has been subject to rapid evolution, and is highly diverse within the human population. Recent advances in the functional expression and ligand identification of ORs allow for functional analysis of OR evolution, and reveal that changes in OR protein sequences translate into high degrees of functional variations. Moreover, in several cases the functional variation of a single OR affects the perception of its cognate odor ligand, providing clues as to how an odor is coded at the receptor level.

Authors
Jiang, Y; Matsunami, H
MLA Citation
Jiang, Y, and Matsunami, H. "Mammalian odorant receptors: functional evolution and variation." Current opinion in neurobiology 34 (October 2015): 54-60. (Review)
PMID
25660959
Source
epmc
Published In
Current Opinion in Neurobiology
Volume
34
Publish Date
2015
Start Page
54
End Page
60
DOI
10.1016/j.conb.2015.01.014

Molecular profiling of activated olfactory neurons identifies odorant receptors for odors in vivo.

The mammalian olfactory system uses a large family of odorant receptors (ORs) to detect and discriminate amongst a myriad of volatile odor molecules. Understanding odor coding requires comprehensive mapping between ORs and corresponding odors. We developed a means of high-throughput in vivo identification of OR repertoires responding to odorants using phosphorylated ribosome immunoprecipitation of mRNA from olfactory epithelium of odor-stimulated mice followed by RNA-Seq. This approach screened the endogenously expressed ORs against an odor in one set of experiments using awake and freely behaving mice. In combination with validations in a heterologous system, we identified sets of ORs for two odorants, acetophenone and 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), encompassing 69 OR-odorant pairs. We also identified shared amino acid residues specific to the acetophenone or TMT receptors and developed models to predict receptor activation by acetophenone. Our results provide a method for understanding the combinatorial coding of odors in vivo.

Authors
Jiang, Y; Gong, NN; Hu, XS; Ni, MJ; Pasi, R; Matsunami, H
MLA Citation
Jiang, Y, Gong, NN, Hu, XS, Ni, MJ, Pasi, R, and Matsunami, H. "Molecular profiling of activated olfactory neurons identifies odorant receptors for odors in vivo." Nature neuroscience 18.10 (October 2015): 1446-1454.
PMID
26322927
Source
epmc
Published In
Nature Neuroscience
Volume
18
Issue
10
Publish Date
2015
Start Page
1446
End Page
1454
DOI
10.1038/nn.4104

Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution.

Allelic variation at 4 loci in the human olfactory receptor gene OR7D4 is associated with perceptual variation in the sex steroid-derived odorants, androstenone, and androstadienone. Androstadienone has been linked with chemosensory identification whereas androstenone makes pork from uncastrated pigs distasteful ("boar taint"). In a sample of 2224 individuals from 43 populations, we identified 45 OR7D4 single nucleotide polymorphisms. Coalescent modeling of frequency-site-spectrum-based statistics identified significant deviation from neutrality in human OR7D4; individual populations with statistically significant deviations from neutrality include Gujarati, Beijing Han, Great Britain, Iberia, and Puerto Rico. Analysis of molecular variation values indicated statistically significant population differentiation driven mainly by the 4 alleles associated with androstenone perception variation; however, fixation values were low suggesting that genetic structure may not have played a strong role in creating these group divisions. We also studied OR7D4 in the genomes of extinct members of the human lineage: Altai Neandertal and Denisovan. No variants were identified in Altai but 2 were in Denisova, one of which is shared by modern humans and one of which is novel. A functional test of modern human and a synthesized mutant Denisova OR7D4 indicated no statistically significant difference in responses to androstenone between the 2 species. Our results suggest non-neutral evolution for an olfactory receptor gene.

Authors
Hoover, KC; Gokcumen, O; Qureshy, Z; Bruguera, E; Savangsuksa, A; Cobb, M; Matsunami, H
MLA Citation
Hoover, KC, Gokcumen, O, Qureshy, Z, Bruguera, E, Savangsuksa, A, Cobb, M, and Matsunami, H. "Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution." Chemical senses 40.7 (September 2015): 481-488.
PMID
26072518
Source
epmc
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
481
End Page
488
DOI
10.1093/chemse/bjv030

Molecular profiling of activated olfactory neurons using phosphorylated ribosome immunoprecipitation and RNA-Seq identifies odorant receptors responding to odors in vivo

Authors
Jiang, Y; Gong, NN; Ni, MJ; Pasi, R; Matsunami, H
MLA Citation
Jiang, Y, Gong, NN, Ni, MJ, Pasi, R, and Matsunami, H. "Molecular profiling of activated olfactory neurons using phosphorylated ribosome immunoprecipitation and RNA-Seq identifies odorant receptors responding to odors in vivo." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
562
End Page
562

Predicting human odor perception from olfactory receptor activation

Authors
Trimmer, C; Willer, JR; Keller, A; Vosshall, LB; Katsanis, N; Matsunami, H; Mainland, JD
MLA Citation
Trimmer, C, Willer, JR, Keller, A, Vosshall, LB, Katsanis, N, Matsunami, H, and Mainland, JD. "Predicting human odor perception from olfactory receptor activation." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
551
End Page
551

Olfactory receptor accessory proteins RTP1 and RTP2 play a crucial role in receptor gene choice, development and odor detection

Authors
Sharma, R; Ishimaru, Y; Davison, I; Ikegami, K; Matsunami, H
MLA Citation
Sharma, R, Ishimaru, Y, Davison, I, Ikegami, K, and Matsunami, H. "Olfactory receptor accessory proteins RTP1 and RTP2 play a crucial role in receptor gene choice, development and odor detection." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
535
End Page
535

Experience-dependent Axon Targeting and Guidance Molecule Expression in the Mouse Olfactory System

Authors
Gong, NN; Matsunami, H
MLA Citation
Gong, NN, and Matsunami, H. "Experience-dependent Axon Targeting and Guidance Molecule Expression in the Mouse Olfactory System." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
629
End Page
629

Identification of key residues involved in activation of G-protein Coupled Odorant Receptors

Authors
de March, CA; Yu, Y; Ni, MJ; Adipietro, KA; Matsunami, H; Ma, M; Golebiowski, J
MLA Citation
de March, CA, Yu, Y, Ni, MJ, Adipietro, KA, Matsunami, H, Ma, M, and Golebiowski, J. "Identification of key residues involved in activation of G-protein Coupled Odorant Receptors." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
654
End Page
654

Permissive Binding Pocket and Low Activation Threshold Underlie Exceptionally Broad Responsiveness of Some G-Protein Coupled Odorant Receptors

Authors
Yu, Y; de March, CA; Ni, MJ; Adipietro, KA; Golebiowski, J; Matsunami, H; Ma, M
MLA Citation
Yu, Y, de March, CA, Ni, MJ, Adipietro, KA, Golebiowski, J, Matsunami, H, and Ma, M. "Permissive Binding Pocket and Low Activation Threshold Underlie Exceptionally Broad Responsiveness of Some G-Protein Coupled Odorant Receptors." September 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
7
Publish Date
2015
Start Page
633
End Page
633

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors.

Odorant receptor (OR) genes and proteins represent more than 2% of our genome and 4% of our proteome and constitute the largest subgroup of G protein-coupled receptors (GPCRs). The mechanism underlying OR activation remains poorly understood, as they do not share some of the highly conserved motifs critical for activation of non-olfactory GPCRs. By combining site-directed mutagenesis, heterologous expression, and molecular dynamics simulations that capture the conformational change of constitutively active mutants, we tentatively identified crucial residues for the function of these receptors using the mouse MOR256-3 (Olfr124) as a model. The toggle switch for sensing agonists involves a highly conserved tyrosine residue in helix VI. The ionic lock is located between the "DRY" motif in helix III and a positively charged "R/K" residue in helix VI. This study provides an unprecedented model that captures the main mechanisms of odorant receptor activation.

Authors
de March, CA; Yu, Y; Ni, MJ; Adipietro, KA; Matsunami, H; Ma, M; Golebiowski, J
MLA Citation
de March, CA, Yu, Y, Ni, MJ, Adipietro, KA, Matsunami, H, Ma, M, and Golebiowski, J. "Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors." Journal of the American Chemical Society 137.26 (July 2015): 8611-8616.
PMID
26090619
Source
epmc
Published In
Journal of the American Chemical Society
Volume
137
Issue
26
Publish Date
2015
Start Page
8611
End Page
8616
DOI
10.1021/jacs.5b04659

Reply to Turin et al.: Vibrational theory of olfaction is implausible.

Authors
Block, E; Jang, S; Matsunami, H; Batista, VS; Zhuang, H
MLA Citation
Block, E, Jang, S, Matsunami, H, Batista, VS, and Zhuang, H. "Reply to Turin et al.: Vibrational theory of olfaction is implausible." Proceedings of the National Academy of Sciences of the United States of America 112.25 (June 4, 2015): E3155-. (Letter)
PMID
26045493
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
25
Publish Date
2015
Start Page
E3155
DOI
10.1073/pnas.1508443112

Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior.

Females may display dramatically different behavior depending on their state of ovulation. This is thought to occur through sex-specific hormones acting on behavioral centers in the brain. Whether incoming sensory activity also differs across the ovulation cycle to alter behavior has not been investigated. Here, we show that female mouse vomeronasal sensory neurons (VSNs) are temporarily and specifically rendered "blind" to a subset of male-emitted pheromone ligands during diestrus yet fully detect and respond to the same ligands during estrus. VSN silencing occurs through the action of the female sex-steroid progesterone. Not all VSNs are targeted for silencing; those detecting cat ligands remain continuously active irrespective of the estrous state. We identify the signaling components that account for the capacity of progesterone to target specific subsets of male-pheromone responsive neurons for inactivation. These findings indicate that internal physiology can selectively and directly modulate sensory input to produce state-specific behavior. PAPERCLIP.

Authors
Dey, S; Chamero, P; Pru, JK; Chien, M-S; Ibarra-Soria, X; Spencer, KR; Logan, DW; Matsunami, H; Peluso, JJ; Stowers, L
MLA Citation
Dey, S, Chamero, P, Pru, JK, Chien, M-S, Ibarra-Soria, X, Spencer, KR, Logan, DW, Matsunami, H, Peluso, JJ, and Stowers, L. "Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior." Cell 161.6 (June 2015): 1334-1344.
PMID
26046438
Source
epmc
Published In
Cell
Volume
161
Issue
6
Publish Date
2015
Start Page
1334
End Page
1344
DOI
10.1016/j.cell.2015.04.052

Implausibility of the vibrational theory of olfaction.

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and (13)C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d30 lacks the 1,380- to 1,550-cm(-1) IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.

Authors
Block, E; Jang, S; Matsunami, H; Sekharan, S; Dethier, B; Ertem, MZ; Gundala, S; Pan, Y; Li, S; Li, Z; Lodge, SN; Ozbil, M; Jiang, H; Penalba, SF; Batista, VS; Zhuang, H
MLA Citation
Block, E, Jang, S, Matsunami, H, Sekharan, S, Dethier, B, Ertem, MZ, Gundala, S, Pan, Y, Li, S, Li, Z, Lodge, SN, Ozbil, M, Jiang, H, Penalba, SF, Batista, VS, and Zhuang, H. "Implausibility of the vibrational theory of olfaction." Proceedings of the National Academy of Sciences of the United States of America 112.21 (May 2015): E2766-E2774.
PMID
25901328
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
21
Publish Date
2015
Start Page
E2766
End Page
E2774
DOI
10.1073/pnas.1503054112

Molecular recognition of ketamine by a subset of olfactory G protein-coupled receptors.

Ketamine elicits various neuropharmacological effects, including sedation, analgesia, general anesthesia, and antidepressant activity. Through an in vitro screen, we identified four mouse olfactory receptors (ORs) that responded to ketamine. In addition to their presence in the olfactory epithelium, these G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are distributed throughout the central nervous system. To better understand the molecular basis of the interactions between ketamine and ORs, we used sequence comparison and molecular modeling to design mutations that (i) increased, reduced, or abolished ketamine responsiveness in responding receptors, and (ii) rendered nonresponding receptors responsive to ketamine. We showed that olfactory sensory neurons (OSNs) that expressed distinct ORs responded to ketamine in vivo, suggesting that ORs may serve as functional targets for ketamine. The ability to both abolish and introduce responsiveness to ketamine in GPCRs enabled us to identify and confirm distinct interaction loci in the binding site, which suggested a signature ketamine-binding pocket that may guide exploration of additional receptors for this general anesthetic drug.

Authors
Ho, J; Perez-Aguilar, JM; Gao, L; Saven, JG; Matsunami, H; Eckenhoff, RG
MLA Citation
Ho, J, Perez-Aguilar, JM, Gao, L, Saven, JG, Matsunami, H, and Eckenhoff, RG. "Molecular recognition of ketamine by a subset of olfactory G protein-coupled receptors." Science signaling 8.370 (March 31, 2015): ra33-.
PMID
25829447
Source
epmc
Published In
Science Signaling
Volume
8
Issue
370
Publish Date
2015
Start Page
ra33
DOI
10.1126/scisignal.2005912

Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of β-arrestin-2 recruitment.

The olfactory system in rodents serves a critical function in social, reproductive and survival behaviours. Processing of chemosensory signals in the brain is dynamically regulated in part by an animal's physiological state. We previously reported that type 3 muscarinic acetylcholine receptors (M3-Rs) physically interact with odorant receptors (ORs) to promote odour-induced responses in a heterologous expression system. However, it is not known how M3-Rs affect the ability of olfactory sensory neurons (OSNs) to respond to odours. Here, we show that an M3-R antagonist attenuates odour-induced responses in OSNs from wild-type, but not M3-R-null, mice. Using a novel molecular assay, we demonstrate that the activation of M3-Rs inhibits the recruitment of β-arrestin-2 to ORs, resulting in a potentiation of odour-induced responses in OSNs. These results suggest a role for acetylcholine in modulating olfactory processing at the initial stages of signal transduction in the olfactory system.

Authors
Jiang, Y; Li, YR; Tian, H; Ma, M; Matsunami, H
MLA Citation
Jiang, Y, Li, YR, Tian, H, Ma, M, and Matsunami, H. "Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of β-arrestin-2 recruitment." Nature communications 6 (March 24, 2015): 6448-.
PMID
25800153
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
6448
DOI
10.1038/ncomms7448

Molecular Dynamics simulations reveal the active and inactive states of Olfactory Receptors

Authors
de March, CA; Baldovini, N; Le Bon, A-M; Yu, Y; Adipietro, K; Ma, M; Matsunami, H; Golebiowski, J
MLA Citation
de March, CA, Baldovini, N, Le Bon, A-M, Yu, Y, Adipietro, K, Ma, M, Matsunami, H, and Golebiowski, J. "Molecular Dynamics simulations reveal the active and inactive states of Olfactory Receptors." March 2015.
Source
wos-lite
Published In
Chemical Senses
Volume
40
Issue
3
Publish Date
2015
Start Page
220
End Page
220

Improving the odorant sensitivity of olfactory receptor-expressing yeast with accessory proteins.

Olfaction depends on the selectivity and sensitivity of olfactory receptors. Previous attempts at constructing a mammalian olfactory receptor-based artificial odorant sensing system in the budding yeast Saccharomyces cerevisiae suffered from low sensitivity and activity. This result may be at least in part due to poor functional expression of olfactory receptors and/or limited solubility of some odorants in the medium. In this study, we examined the effects of two types of accessory proteins, receptor transporting protein 1 short and odorant binding proteins, in improving odor-mediated activation of olfactory receptors expressed in yeast. We found that receptor transporting protein 1 short enhanced the membrane expression and ligand-induced responses of some olfactory receptors. Coexpression of odorant binding proteins of the silkworm moth Bombyx mori enhanced the sensitivity of a mouse olfactory receptor. Our results suggest that different classes of accessory proteins can confer sensitive and robust responses of olfactory receptors expressed in yeast. Inclusion of accessory proteins may be essential in the future development of practical olfactory receptor-based odorant sensors.

Authors
Fukutani, Y; Hori, A; Tsukada, S; Sato, R; Ishii, J; Kondo, A; Matsunami, H; Yohda, M
MLA Citation
Fukutani, Y, Hori, A, Tsukada, S, Sato, R, Ishii, J, Kondo, A, Matsunami, H, and Yohda, M. "Improving the odorant sensitivity of olfactory receptor-expressing yeast with accessory proteins." Analytical biochemistry 471 (February 2015): 1-8.
PMID
25449303
Source
epmc
Published In
Analytical Biochemistry
Volume
471
Publish Date
2015
Start Page
1
End Page
8
DOI
10.1016/j.ab.2014.10.012

Human olfactory receptor responses to odorants.

Although the human olfactory system is capable of discriminating a vast number of odors, we do not currently understand what chemical features are encoded by olfactory receptors. In large part this is due to a paucity of data in a search space covering the interactions of hundreds of receptors with billions of odorous molecules. Of the approximately 400 intact human odorant receptors, only 10% have a published ligand. Here we used a heterologous luciferase assay to screen 73 odorants against a clone library of 511 human olfactory receptors. This dataset will allow other researchers to interrogate the combinatorial nature of olfactory coding.

Authors
Mainland, JD; Li, YR; Zhou, T; Liu, WLL; Matsunami, H
MLA Citation
Mainland, JD, Li, YR, Zhou, T, Liu, WLL, and Matsunami, H. "Human olfactory receptor responses to odorants." Scientific data 2 (January 2015): 150002-.
PMID
25977809
Source
epmc
Published In
Scientific Data
Volume
2
Publish Date
2015
Start Page
150002
DOI
10.1038/sdata.2015.2

Cell-based system for identification of olfactory receptors

© 2014 Springer Science+Business Media Dordrecht. The discovery and characterization of odorant receptors (ORs) beginning in the early 1990s have opened up the ability to study olfaction from a molecular perspective. Hundreds of OR genes that differ between organisms exist, and each gene codes for a G protein coupled receptor (GPCR) that can be activated by a large variety of odorants. Thus, the process of deorphaning, or identifying the cognate ligand(s) for each receptor, is critical for understanding how smells are perceived. This chapter reviews the usage of heterologous systems and associated accessory proteins for expressing ORs in vitro, notably the luciferase assay system for high-throughput OR screening. This in vitro method of characterizing ORs is also compared to ex vivo preparations, with a discussion of advantages and drawbacks of each supported by experimental evidence.

Authors
Dong, PY; Gong, NN; Matsunami, H
MLA Citation
Dong, PY, Gong, NN, and Matsunami, H. "Cell-based system for identification of olfactory receptors." Bioelectronic Nose: Integration of Biotechnology and Nanotechnology. December 1, 2014. 83-95.
Source
scopus
Volume
9789401786133
Publish Date
2014
Start Page
83
End Page
95
DOI
10.1007/978-94-017-8613-3_5

Mechanisms of olfaction

© 2014 Springer Science+Business Media Dordrecht. Molecular mechanisms of olfaction have been intensively studied in the last quarter century. Receptors by which olfactory stimuli are detected are vastly different between different animal species and even between different olfactory organs of the same species. This chapter includes a description of the anatomy of the mammalian olfactory system and an overview of the receptors. The signaling mechanism and expression pattern of these receptors is discussed along with how the brain decodes olfactory information gathered from the environment and then translates these signals into behaviors. This chapter also contains brief comparison of the fish, insect and nematode olfactory receptors.

Authors
Sharma, R; Matsunami, H
MLA Citation
Sharma, R, and Matsunami, H. "Mechanisms of olfaction." Bioelectronic Nose: Integration of Biotechnology and Nanotechnology. December 1, 2014. 23-45.
Source
scopus
Volume
9789401786133
Publish Date
2014
Start Page
23
End Page
45
DOI
10.1007/978-94-017-8613-3_2

Aldehyde recognition and discrimination by mammalian odorant receptors via functional group-specific hydration chemistry.

The mammalian odorant receptors (ORs) form a chemical-detecting interface between the atmosphere and the nervous system. This large gene family is composed of hundreds of membrane proteins predicted to form as many unique small molecule binding niches within their G-protein coupled receptor (GPCR) framework, but very little is known about the molecular recognition strategies they use to bind and discriminate between small molecule odorants. Using rationally designed synthetic analogs of a typical aliphatic aldehyde, we report evidence that among the ORs showing specificity for the aldehyde functional group, a significant percentage detect the aldehyde through its ability to react with water to form a 1,1-geminal (gem)-diol. Evidence is presented indicating that the rat OR-I7, an often-studied and modeled OR known to require the aldehyde function of octanal for activation, is likely one of the gem-diol activated receptors. A homology model based on an activated GPCR X-ray structure provides a structural hypothesis for activation of OR-I7 by the gem-diol of octanal.

Authors
Li, Y; Peterlin, Z; Ho, J; Yarnitzky, T; Liu, MT; Fichman, M; Niv, MY; Matsunami, H; Firestein, S; Ryan, K
MLA Citation
Li, Y, Peterlin, Z, Ho, J, Yarnitzky, T, Liu, MT, Fichman, M, Niv, MY, Matsunami, H, Firestein, S, and Ryan, K. "Aldehyde recognition and discrimination by mammalian odorant receptors via functional group-specific hydration chemistry." ACS chemical biology 9.11 (November 2014): 2563-2571.
PMID
25181321
Source
epmc
Published In
ACS Chemical Biology
Volume
9
Issue
11
Publish Date
2014
Start Page
2563
End Page
2571
DOI
10.1021/cb400290u

In vivo identification of eugenol-responsive and muscone-responsive mouse odorant receptors.

Our understanding of mammalian olfactory coding has been impeded by the paucity of information about the odorant receptors (ORs) that respond to a given odorant ligand in awake, freely behaving animals. Identifying the ORs that respond in vivo to a given odorant ligand from among the ∼1100 ORs in mice is intrinsically challenging but critical for our understanding of olfactory coding at the periphery. Here, we report an in vivo assay that is based on a novel gene-targeted mouse strain, S100a5-tauGFP, in which a fluorescent reporter selectively marks olfactory sensory neurons that have been activated recently in vivo. Because each olfactory sensory neuron expresses a single OR gene, multiple ORs responding to a given odorant ligand can be identified simultaneously by capturing the population of activated olfactory sensory neurons and using expression profiling methods to screen the repertoire of mouse OR genes. We used this in vivo assay to re-identify known eugenol- and muscone-responsive mouse ORs. We identified additional ORs responsive to eugenol or muscone. Heterologous expression assays confirmed nine eugenol-responsive ORs (Olfr73, Olfr178, Olfr432, Olfr610, Olfr958, Olfr960, Olfr961, Olfr913, and Olfr1234) and four muscone-responsive ORs (Olfr74, Olfr235, Olfr816, and Olfr1440). We found that the human ortholog of Olfr235 and Olfr1440 responds to macrocyclic ketone and lactone musk odorants but not to polycyclic musk odorants or a macrocyclic diester musk odorant. This novel assay, called the Kentucky in vivo odorant ligand-receptor assay, should facilitate the in vivo identification of mouse ORs for a given odorant ligand of interest.

Authors
McClintock, TS; Adipietro, K; Titlow, WB; Breheny, P; Walz, A; Mombaerts, P; Matsunami, H
MLA Citation
McClintock, TS, Adipietro, K, Titlow, WB, Breheny, P, Walz, A, Mombaerts, P, and Matsunami, H. "In vivo identification of eugenol-responsive and muscone-responsive mouse odorant receptors." The Journal of neuroscience : the official journal of the Society for Neuroscience 34.47 (November 2014): 15669-15678.
PMID
25411495
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
34
Issue
47
Publish Date
2014
Start Page
15669
End Page
15678
DOI
10.1523/jneurosci.3625-14.2014

Aldehyde Recognition and Discrimination by Mammalian Odorant Receptors via Functional Group-Specific Hydration Chemistry

Authors
Li, Y; Peterlin, Z; Ho, J; Yarnitzky, T; Liu, MT; Fichman, M; Niv, MY; Matsunami, H; Firestein, S; Ryan, K
MLA Citation
Li, Y, Peterlin, Z, Ho, J, Yarnitzky, T, Liu, MT, Fichman, M, Niv, MY, Matsunami, H, Firestein, S, and Ryan, K. "Aldehyde Recognition and Discrimination by Mammalian Odorant Receptors via Functional Group-Specific Hydration Chemistry." ACS CHEMICAL BIOLOGY 9.11 (November 2014): 2563-2571.
Source
wos-lite
Published In
ACS Chemical Biology
Volume
9
Issue
11
Publish Date
2014
Start Page
2563
End Page
2571
DOI
10.1021/cb400290u

Calreticulin: roles in cell-surface protein expression.

In order to perform their designated functions, proteins require precise subcellular localizations. For cell-surface proteins, such as receptors and channels, they are able to transduce signals only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein folding, maturation, and trafficking. However, evidence has been accumulating that calreticulin can also negatively regulate the surface expression of certain receptors and channels. In these instances, depletion of calreticulin enhances cell-surface expression and function. In this review, we discuss the role of calreticulin with a focus on its negative effects on the expression of cell-surface proteins.

Authors
Jiang, Y; Dey, S; Matsunami, H
MLA Citation
Jiang, Y, Dey, S, and Matsunami, H. "Calreticulin: roles in cell-surface protein expression." Membranes 4.3 (September 16, 2014): 630-641. (Review)
PMID
25230046
Source
epmc
Published In
Membranes
Volume
4
Issue
3
Publish Date
2014
Start Page
630
End Page
641
DOI
10.3390/membranes4030630

QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments.

Understanding structure/function relationships of olfactory receptors is challenging due to the lack of x-ray structural models. Here, we introduce a QM/MM model of the mouse olfactory receptor MOR244-3, responsive to organosulfur odorants such as (methylthio)methanethiol. The binding site consists of a copper ion bound to the heteroatoms of amino-acid residues H105, C109, and N202. The model is consistent with site-directed mutagenesis experiments and biochemical measurements of the receptor activation, and thus provides a valuable framework for further studies of the sense of smell at the molecular level.

Authors
Sekharan, S; Ertem, MZ; Zhuang, H; Block, E; Matsunami, H; Zhang, R; Wei, JN; Pan, Y; Batista, VS
MLA Citation
Sekharan, S, Ertem, MZ, Zhuang, H, Block, E, Matsunami, H, Zhang, R, Wei, JN, Pan, Y, and Batista, VS. "QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments." Biophysical journal 107.5 (September 2014): L5-L8. (Letter)
PMID
25185561
Source
epmc
Published In
Biophysical Journal
Volume
107
Issue
5
Publish Date
2014
Start Page
L5
End Page
L8
DOI
10.1016/j.bpj.2014.07.031

Astringency: a more stringent definition.

Despite being an everyday sensory experience, the nature of astringency perception is not clear. In this issue of Chemical Senses, Schöbel et al. demonstrate that astringency is a trigeminal sensation in human, and astringents trigger a G protein-coupled pathway in trigeminal ganglion cells in the mouse.

Authors
Jiang, Y; Gong, NN; Matsunami, H
MLA Citation
Jiang, Y, Gong, NN, and Matsunami, H. "Astringency: a more stringent definition." Chemical senses 39.6 (July 2014): 467-469.
PMID
24860069
Source
epmc
Published In
Chemical Senses
Volume
39
Issue
6
Publish Date
2014
Start Page
467
End Page
469
DOI
10.1093/chemse/bju021

The missense of smell: Functional variability in the human odorant receptor repertoire

Authors
Mainland, JD; Keller, A; Li, YR; Zhou, T; Trimmer, C; Snyder, LL; Moberly, AH; Adipietro, KA; Liu, WLL; Zhuang, H; Zhan, S; Lee, SS; Lin, A; Matsunami, H
MLA Citation
Mainland, JD, Keller, A, Li, YR, Zhou, T, Trimmer, C, Snyder, LL, Moberly, AH, Adipietro, KA, Liu, WLL, Zhuang, H, Zhan, S, Lee, SS, Lin, A, and Matsunami, H. "The missense of smell: Functional variability in the human odorant receptor repertoire." Nature Neuroscience 17.1 (January 1, 2014): 114-120.
Source
scopus
Published In
Nature Neuroscience
Volume
17
Issue
1
Publish Date
2014
Start Page
114
End Page
120
DOI
10.1038/nn.3598

The molecular basis of sour sensing in mammals

Authors
Ho, J; Matsunami, H; Ishimaru, Y
MLA Citation
Ho, J, Matsunami, H, and Ishimaru, Y. "The molecular basis of sour sensing in mammals." Molecular Genetics of Dysregulated pH Homeostasis. January 1, 2014. 27-43.
Source
scopus
Publish Date
2014
Start Page
27
End Page
43
DOI
10.1007/978-1-4939-1683-2_3

The missense of smell: functional variability in the human odorant receptor repertoire.

Humans have ~400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals have functional differences at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high-affinity in vitro agonist guaiacol but do not explain phenotype variation for the lower-affinity agonists vanillin and ethyl vanillin.

Authors
Mainland, JD; Keller, A; Li, YR; Zhou, T; Trimmer, C; Snyder, LL; Moberly, AH; Adipietro, KA; Liu, WLL; Zhuang, H; Zhan, S; Lee, SS; Lin, A; Matsunami, H
MLA Citation
Mainland, JD, Keller, A, Li, YR, Zhou, T, Trimmer, C, Snyder, LL, Moberly, AH, Adipietro, KA, Liu, WLL, Zhuang, H, Zhan, S, Lee, SS, Lin, A, and Matsunami, H. "The missense of smell: functional variability in the human odorant receptor repertoire." Nat Neurosci 17.1 (January 2014): 114-120.
Website
http://hdl.handle.net/10161/8268
PMID
24316890
Source
pubmed
Published In
Nature Neuroscience
Volume
17
Issue
1
Publish Date
2014
Start Page
114
End Page
120
DOI
10.1038/nn.3598

QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments

Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.Understanding structure/function relationships of olfactory receptors is challenging due to the lack of x-ray structural models. Here, we introduce a QM/MM model of the mouse olfactory receptor MOR244-3, responsive to organosulfur odorants such as (methylthio)methanethiol. The binding site consists of a copper ion bound to the heteroatoms of amino-acid residues H105, C109, and N202. The model is consistent with site-directed mutagenesis experiments and biochemical measurements of the receptor activation, and thus provides a valuable framework for further studies of the sense of smell at the molecular level.

Authors
Sekharan, S; Ertem, MZ; Zhuang, H; Block, E; Matsunami, H; Zhang, R; Wei, JN; Pan, Y; Batista, VS
MLA Citation
Sekharan, S, Ertem, MZ, Zhuang, H, Block, E, Matsunami, H, Zhang, R, Wei, JN, Pan, Y, and Batista, VS. "QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments." Biophysical journal 107.5 (2014): L5-L8.
Source
scival
Published In
Biophysical Journal
Volume
107
Issue
5
Publish Date
2014
Start Page
L5
End Page
L8
DOI
10.1016/j.bpj.2014.07.031

Next-generation sequencing of the human olfactory receptors

Humans have approximately 400 intact olfactory receptors (ORs). Among this set there are a large number of variations between individuals, a subset of which affects receptor function and can lead to interindividual variation in olfactory perception. Technological progress and cost erosion in next-generation sequencing have given us the opportunity to determine the sequence of the entire OR gene set with high fi delity and to measure the extent of variation in this functional module across many individuals. Given that whole genome sequencing remains prohibitively expensive for this purpose, especially since the OR sub-genome represents only ~0.0125 % of the human genome, we have designed a targeted capture method to enrich the OR for next-generation sequencing, which we describe here. Using this method we have been able to sequence an individual's OR sub-genome with high coverage, enabling us to identify variation with high sensitivity and speci fi city. This method can be used to accurate assess the amount of variability in this module and to identify the functional role of individual ORs in olfactory perception. © Springer Science+Business Media, LLC 2013.

Authors
Mainland, JD; Willer, JR; Matsunami, H; Katsanis, NR
MLA Citation
Mainland, JD, Willer, JR, Matsunami, H, and Katsanis, NR. "Next-generation sequencing of the human olfactory receptors." Methods in Molecular Biology 1003 (December 1, 2013): 133-147.
Source
scopus
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1003
Publish Date
2013
Start Page
133
End Page
147
DOI
10.1007/978-1-62703-377-0-10

Odorant-receptor interaction

© 2014 Springer Science+Business Media Dordrecht. Odorant-receptor interactions constitute a key step in the olfactory detection of chemical compounds. Various studies support the combinatorial coding of olfaction, in which each odorant activates an array of odorant receptors and each odorant receptor is capable of recognizing multiple odorants, while large-scale studies involving numerous odorants and odorant receptors help to resolve the tuning specificities of receptor repertoires. In the meantime, the proteinaceous content of the nasal mucus, including odorant binding proteins and different types of xenobiotic-metabolizing enzymes, also contributes to odorant receptor activation by transporting, concentrating, converting, and/or ultimately removing odorants from nasal mucosa. In addition, the presence of metal ions, notably copper ions, is known to be important for the activation of odorant receptors for certain types of metal-coordinating odorants. Finally, prediction algorithms based on odorant properties and receptor structures are becoming increasingly feasible for investigating detailed mechanisms involved in odorant-receptor interactions.

Authors
Su, X; Matsunami, H; Zhuang, H
MLA Citation
Su, X, Matsunami, H, and Zhuang, H. "Odorant-receptor interaction." Bioelectronic Nose: Integration of Biotechnology and Nanotechnology. December 1, 2013. 69-81.
Source
scopus
Publish Date
2013
Start Page
69
End Page
81
DOI
10.1007/978-94-017-8613-3_4

Unfolding the mystery of olfactory receptor gene expression.

Reporting recently in Cell, Dalton et al. (2013) identify a central role for the unfolded protein response in the regulation of olfactory receptor expression, unveiling molecular players in an elaborate feedback loop that controls the stabilization and establishment of single olfactory receptor gene choice.

Authors
Li, YR; Matsunami, H
MLA Citation
Li, YR, and Matsunami, H. "Unfolding the mystery of olfactory receptor gene expression." Dev Cell 27.2 (October 28, 2013): 128-129.
PMID
24176639
Source
pubmed
Published In
Developmental Cell
Volume
27
Issue
2
Publish Date
2013
Start Page
128
End Page
129
DOI
10.1016/j.devcel.2013.10.012

Using conformationally restricted odorant ligands to probe the olfactory GPCRs

Authors
Ryan, K; Li, Y; Peterlin, Z; Ho, J; Firestein, S; Matsunami, H; Liu, MT
MLA Citation
Ryan, K, Li, Y, Peterlin, Z, Ho, J, Firestein, S, Matsunami, H, and Liu, MT. "Using conformationally restricted odorant ligands to probe the olfactory GPCRs." September 8, 2013.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
246
Publish Date
2013

General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations.

Genetic variations in olfactory receptors likely contribute to the diversity of odorant-specific sensitivity phenotypes. Our working hypothesis is that genetic variations in auxiliary olfactory genes, including those mediating transduction and sensory neuronal development, may constitute the genetic basis for general olfactory sensitivity (GOS) and congenital general anosmia (CGA). We thus performed a systematic exploration for auxiliary olfactory genes and their documented variation. This included a literature survey, seeking relevant functional in vitro studies, mouse gene knockouts and human disorders with olfactory phenotypes, as well as data mining in published transcriptome and proteome data for genes expressed in olfactory tissues. In addition, we performed next-generation transcriptome sequencing (RNA-seq) of human olfactory epithelium and mouse olfactory epithelium and bulb, so as to identify sensory-enriched transcripts. Employing a global score system based on attributes of the 11 data sources utilized, we identified a list of 1,680 candidate auxiliary olfactory genes, of which 450 are shortlisted as having higher probability of a functional role. For the top-scoring 136 genes, we identified genomic variants (probably damaging single nucleotide polymorphisms, indels, and copy number deletions) gleaned from public variation repositories. This database of genes and their variants should assist in rationalizing the great interindividual variation in human overall olfactory sensitivity (http://genome.weizmann.ac.il/GOSdb).

Authors
Keydar, I; Ben-Asher, E; Feldmesser, E; Nativ, N; Oshimoto, A; Restrepo, D; Matsunami, H; Chien, M-S; Pinto, JM; Gilad, Y; Olender, T; Lancet, D
MLA Citation
Keydar, I, Ben-Asher, E, Feldmesser, E, Nativ, N, Oshimoto, A, Restrepo, D, Matsunami, H, Chien, M-S, Pinto, JM, Gilad, Y, Olender, T, and Lancet, D. "General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations." Hum Mutat 34.1 (January 2013): 32-41.
PMID
22936402
Source
pubmed
Published In
Human Mutation
Volume
34
Issue
1
Publish Date
2013
Start Page
32
End Page
41
DOI
10.1002/humu.22212

Characterization of allelic-biased genes in single olfactory neurons

Authors
Chien, M-S; Matsunami, H
MLA Citation
Chien, M-S, and Matsunami, H. "Characterization of allelic-biased genes in single olfactory neurons." MOLECULAR BIOLOGY OF THE CELL 24 (2013).
Source
wos-lite
Published In
Molecular Biology of the Cell
Volume
24
Publish Date
2013

Next-generation sequencing of the human olfactory receptors.

Humans have approximately 400 intact olfactory receptors (ORs). Among this set there are a large number of variations between individuals, a subset of which affects receptor function and can lead to interindividual variation in olfactory perception. Technological progress and cost erosion in next-generation sequencing have given us the opportunity to determine the sequence of the entire OR gene set with high fidelity and to measure the extent of variation in this functional module across many individuals. Given that whole genome sequencing remains prohibitively expensive for this purpose, especially since the OR sub-genome represents only ~0.0125 % of the human genome, we have designed a targeted capture method to enrich the OR for next-generation sequencing, which we describe here. Using this method we have been able to sequence an individual's OR sub-genome with high coverage, enabling us to identify variation with high sensitivity and specificity. This method can be used to accurate assess the amount of variability in this module and to identify the functional role of individual ORs in olfactory perception.

Authors
Mainland, JD; Willer, JR; Matsunami, H; Katsanis, N
MLA Citation
Mainland, JD, Willer, JR, Matsunami, H, and Katsanis, N. "Next-generation sequencing of the human olfactory receptors." Methods Mol Biol 1003 (2013): 133-147.
PMID
23585039
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1003
Publish Date
2013
Start Page
133
End Page
147
DOI
10.1007/978-1-62703-377-0_10

A protocol for heterologous expression and functional assay for mouse pheromone receptors.

Innate social behaviors like intermale aggression, fear, and mating rituals are important for survival and propagation of a species. In mice, these behaviors have been implicated to be mediated by peptide pheromones that are sensed by a class of G protein-coupled receptors, vomeronasal receptor type 2 (V2Rs), expressed in the pheromone-detecting vomeronasal organ (VNO) (Chamero et al., Nature 450:899-902, 2007; Haga et al., Nature 466:118-122, 2010; Kimoto et al., Curr Biol 17:1879-1884, 2007; Leinders-Zufall et al., Nat Neurosci 12:1551-1558, 2009; Papes et al., Cell 141:692-703, 2010). Matching V2Rs with their cognate ligands is required to understand what receptors the biologically relevant pheromones are acting on. However, this goal has been greatly limited by the unavailability of appropriate heterologous tools commonly used to carry out receptor deorphanization, due to the fact that this family of receptors fails to traffic to the surface of heterologous cells. We have demonstrated that calreticulin, a housekeeping chaperone commonly expressed in most eukaryotic cells, is sparsely expressed in the vomeronasal sensory neurons (VSNs). Stable knock down of calreticulin in a HEK293T derived cell line (R24 cells) allows us to functionally express V2Rs on the surface of heterologous cells. In this chapter we describe protocols for maintenance and expansion of the R24 cell line and functional assays for V2Rs using these cells.

Authors
Dey, S; Zhan, S; Matsunami, H
MLA Citation
Dey, S, Zhan, S, and Matsunami, H. "A protocol for heterologous expression and functional assay for mouse pheromone receptors." Methods Mol Biol 1068 (2013): 121-131.
PMID
24014358
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1068
Publish Date
2013
Start Page
121
End Page
131
DOI
10.1007/978-1-62703-619-1_9

Genetic variation in the odorant receptor OR2J3 is associated with the ability to detect the "grassy" smelling odor, cis-3-hexen-1-ol.

The ability to detect many odors varies among individuals; however, the contribution of genotype to this variation has been assessed for relatively few compounds. We have identified a genetic basis for the ability to detect the flavor compound cis-3-hexen-1-ol. This compound is typically described as "green grassy" or the smell of "cut grass," with variation in the ability to detect it linked to single nucleotide polymorphisms (SNPs) in a region on human chromosome 6 containing 25 odorant receptor genes. We have sequenced the coding regions of all 25 receptors across an ethnically mixed population of 52 individuals and identified 147 sequence variants. We tested these for association with cis-3-hexen-1-ol detection thresholds and found 3 strongly associated SNPs, including one found in a functional odorant receptor (rs28757581 in OR2J3). In vitro assays of 13 odorant receptors from the region identified 3 receptors that could respond to cis-3-hexen-1-ol, including OR2J3. This gene contained 5 predicted haplotypes across the 52 individuals. We tested all 5 haplotypes in vitro and several amino acid substitutions on their own, such as rs28757581 (T113A). Two amino acid substitutions, T113A and R226Q, impaired the ability of OR2J3 to respond to cis-3-hexen-1-ol, and together these two substitutions effectively abolished the response to the compound. The haplotype of OR2J3 containing both T113A and R226Q explains 26.4% of the variation in cis-3-hexen-1-ol detection in our study cohort. Further research is required to examine whether OR2J3 haplotypes explain variation in perceived flavor experience and the consumption of foods containing cis-3-hexen-1-ol.

Authors
McRae, JF; Mainland, JD; Jaeger, SR; Adipietro, KA; Matsunami, H; Newcomb, RD
MLA Citation
McRae, JF, Mainland, JD, Jaeger, SR, Adipietro, KA, Matsunami, H, and Newcomb, RD. "Genetic variation in the odorant receptor OR2J3 is associated with the ability to detect the "grassy" smelling odor, cis-3-hexen-1-ol." Chem Senses 37.7 (September 2012): 585-593.
PMID
22714804
Source
pubmed
Published In
Chemical Senses
Volume
37
Issue
7
Publish Date
2012
Start Page
585
End Page
593
DOI
10.1093/chemse/bjs049

Receptor-transporting protein 1 short (RTP1S) mediates translocation and activation of odorant receptors by acting through multiple steps.

Odorant receptor (OR) proteins are retained in the endoplasmic reticulum when heterologously expressed in cultured cells of non-olfactory origins. RTP1S is an accessory protein to mammalian ORs and facilitates their trafficking to the cell-surface membrane and ligand-induced responses in heterologous cells. The mechanism by which RTP1S promotes the functional expression of ORs remains poorly understood. To obtain a better understanding of the role(s) of RTP1S, we performed a series of structure-function analyses of RTP1S in HEK293T cells. By constructing RTP1S deletion and chimera series and subsequently introducing single-site mutations into the protein, we found the N terminus of RTP1S is important for the endoplasmic reticulum exit of ORs and that a middle region of RTP1S is important for OR trafficking from the Golgi to the membrane. Using sucrose gradient centrifugation, we found that the localization of RTP1S to the lipid raft microdomain is critical to the activation of ORs. Finally, in a protein-protein interaction analysis, we determined that the C terminus of RTP1S may be interacting with ORs. These findings provide new insights into the distinct roles of RTP1S in OR translocation and activation.

Authors
Wu, L; Pan, Y; Chen, G-Q; Matsunami, H; Zhuang, H
MLA Citation
Wu, L, Pan, Y, Chen, G-Q, Matsunami, H, and Zhuang, H. "Receptor-transporting protein 1 short (RTP1S) mediates translocation and activation of odorant receptors by acting through multiple steps." J Biol Chem 287.26 (June 22, 2012): 22287-22294.
PMID
22570474
Source
pubmed
Published In
The Journal of biological chemistry
Volume
287
Issue
26
Publish Date
2012
Start Page
22287
End Page
22294
DOI
10.1074/jbc.M112.345884

Crucial role of copper in detection of metal-coordinating odorants.

Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH(2)SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol-OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT-copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.

Authors
Duan, X; Block, E; Li, Z; Connelly, T; Zhang, J; Huang, Z; Su, X; Pan, Y; Wu, L; Chi, Q; Thomas, S; Zhang, S; Ma, M; Matsunami, H; Chen, G-Q; Zhuang, H
MLA Citation
Duan, X, Block, E, Li, Z, Connelly, T, Zhang, J, Huang, Z, Su, X, Pan, Y, Wu, L, Chi, Q, Thomas, S, Zhang, S, Ma, M, Matsunami, H, Chen, G-Q, and Zhuang, H. "Crucial role of copper in detection of metal-coordinating odorants." Proc Natl Acad Sci U S A 109.9 (February 28, 2012): 3492-3497.
PMID
22328155
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
9
Publish Date
2012
Start Page
3492
End Page
3497
DOI
10.1073/pnas.1111297109

Functional evolution of mammalian odorant receptors.

The mammalian odorant receptor (OR) repertoire is an attractive model to study evolution, because ORs have been subjected to rapid evolution between species, presumably caused by changes of the olfactory system to adapt to the environment. However, functional assessment of ORs in related species remains largely untested. Here we investigated the functional properties of primate and rodent ORs to determine how well evolutionary distance predicts functional characteristics. Using human and mouse ORs with previously identified ligands, we cloned 18 OR orthologs from chimpanzee and rhesus macaque and 17 mouse-rat orthologous pairs that are broadly representative of the OR repertoire. We functionally characterized the in vitro responses of ORs to a wide panel of odors and found similar ligand selectivity but dramatic differences in response magnitude. 87% of human-primate orthologs and 94% of mouse-rat orthologs showed differences in receptor potency (EC50) and/or efficacy (dynamic range) to an individual ligand. Notably dN/dS ratio, an indication of selective pressure during evolution, does not predict functional similarities between orthologs. Additionally, we found that orthologs responded to a common ligand 82% of the time, while human OR paralogs of the same subfamily responded to the common ligand only 33% of the time. Our results suggest that, while OR orthologs tend to show conserved ligand selectivity, their potency and/or efficacy dynamically change during evolution, even in closely related species. These functional changes in orthologs provide a platform for examining how the evolution of ORs can meet species-specific demands.

Authors
Adipietro, KA; Mainland, JD; Matsunami, H
MLA Citation
Adipietro, KA, Mainland, JD, and Matsunami, H. "Functional evolution of mammalian odorant receptors." PLoS Genet 8.7 (2012): e1002821-.
Website
http://hdl.handle.net/10161/5830
PMID
22807691
Source
pubmed
Published In
PLoS genetics
Volume
8
Issue
7
Publish Date
2012
Start Page
e1002821
DOI
10.1371/journal.pgen.1002821

RAMP like proteins : RTP and REEP family of proteins.

Mammalian odorant receptors (ORs) are typically retained in the endoplasmic reticulum (ER) when expressed in heterologous cells. The RTP (Receptor-Transporting Protein) and REEP (Receptor Expression Enhancing Protein) family of proteins were first identified as partners for ORs, promoting cell-surface expression and leading to functional responses in heterologous cell systems. Like RAMPs, the RTP and REEP proteins appear to partner with GPCRs to promote cell-surface expression. Unlike RAMPs, they do not appear to alter the pharmacology of the partner receptor.

Authors
Mainland, J; Matsunami, H
MLA Citation
Mainland, J, and Matsunami, H. "RAMP like proteins : RTP and REEP family of proteins." Adv Exp Med Biol 744 (2012): 75-86. (Review)
PMID
22434109
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
744
Publish Date
2012
Start Page
75
End Page
86
DOI
10.1007/978-1-4614-2364-5_7

Genetic variation of an odorant receptor OR7D4 and sensory perception of cooked meat containing androstenone.

Although odour perception impacts food preferences, the effect of genotypic variation of odorant receptors (ORs) on the sensory perception of food is unclear. Human OR7D4 responds to androstenone, and genotypic variation in OR7D4 predicts variation in the perception of androstenone. Since androstenone is naturally present in meat derived from male pigs, we asked whether OR7D4 genotype correlates with either the ability to detect androstenone or the evaluation of cooked pork tainted with varying levels of androstenone within the naturally-occurring range. Consistent with previous findings, subjects with two copies of the functional OR7D4 RT variant were more sensitive to androstenone than subjects carrying a non-functional OR7D4 WM variant. When pork containing varying levels of androstenone was cooked and tested by sniffing and tasting, subjects with two copies of the RT variant tended to rate the androstenone-containing meat as less favourable than subjects carrying the WM variant. Our data is consistent with the idea that OR7D4 genotype predicts the sensory perception of meat containing androstenone and that genetic variation in an odorant receptor can alter food preferences.

Authors
Lunde, K; Egelandsdal, B; Skuterud, E; Mainland, JD; Lea, T; Hersleth, M; Matsunami, H
MLA Citation
Lunde, K, Egelandsdal, B, Skuterud, E, Mainland, JD, Lea, T, Hersleth, M, and Matsunami, H. "Genetic variation of an odorant receptor OR7D4 and sensory perception of cooked meat containing androstenone." PLoS One 7.5 (2012): e35259-.
PMID
22567099
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e35259
DOI
10.1371/journal.pone.0035259

Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors.

A variety of social behaviors like intermale aggression, fear, and mating rituals are important for sustenance of a species. In mice, these behaviors have been implicated to be mediated by peptide pheromones that are sensed by a class of G protein-coupled receptors, vomeronasal receptor type 2 (V2Rs), expressed in the pheromone detecting vomeronasal organ. Matching V2Rs with their cognate ligands is required to learn what receptors the biologically relevant pheromones are acting on. However, this feat has been greatly limited by the unavailability of appropriate heterologous tools commonly used to study ligand receptor specificity, because this family of receptors fails to traffic to the surface of heterologous cells. Here we show that calreticulin, a housekeeping chaperone commonly expressed in most eukaryotic cells, is sparsely expressed in the vomeronasal sensory neurons (VSNs). Correspondingly, knockdown of calreticulin in commonly available cell lines enables V2Rs to efficiently target to the cell membrane. Using this knowledge, we have now been able to successfully surface express receptors and functionally identify cognate ligands. Additionally, calreticulin4, a homolog of calreticulin shows restricted and enriched expression in the VSNs. Interestingly, in heterologous cells, calreticulin4 does not inhibit surface expression of V2Rs and can in part carry out functions of calreticulin. On the basis of our data, we postulate that V2Rs may use a unique trafficking mechanism whereby an important and more commonly expressed chaperone is deleterious for membrane export and is replaced by a functionally equivalent homolog that does not inhibit export while carrying out its functions.

Authors
Dey, S; Matsunami, H
MLA Citation
Dey, S, and Matsunami, H. "Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors." Proc Natl Acad Sci U S A 108.40 (October 4, 2011): 16651-16656.
PMID
21933956
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
40
Publish Date
2011
Start Page
16651
End Page
16656
DOI
10.1073/pnas.1018140108

Smelling sulfur: An odorant receptor for divalent sulfur compounds employs copper ion as a cofactor

Authors
Block, E; Zhuang, H; Matsunami, H; Chen, G-Q; Duan, X; Zhang, J; Huang, Z; Li, Z; Pan, Y; Chi, Q; Thomas, S; Zhang, S
MLA Citation
Block, E, Zhuang, H, Matsunami, H, Chen, G-Q, Duan, X, Zhang, J, Huang, Z, Li, Z, Pan, Y, Chi, Q, Thomas, S, and Zhang, S. "Smelling sulfur: An odorant receptor for divalent sulfur compounds employs copper ion as a cofactor." August 28, 2011.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
242
Publish Date
2011

G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice.

The rodent vomeronasal organ (VNO) mediates the regulation of species-specific and interspecies social behaviors. We have used gene targeting to examine the role of the G protein Gαo, encoded by the gene Gnao1, in vomeronasal function. We used the Cre-loxP system to delete Gαo in those cells that express olfactory marker protein, which includes all vomeronasal sensory neurons of the basal layer of the VNO sensory epithelium. Using electrophysiology and calcium imaging, we show that the conditional null mice exhibit strikingly reduced sensory responses in V2R receptor-expressing vomeronasal sensory neurons to specific molecular cues, including MHC1 antigens, major urinary proteins, and exocrine gland-secreting peptide. Gαo is also vital for vomeronasal sensing of two N-formylated mitochondrially encoded peptides derived from NADH dehydrogenase 1. Furthermore, we show that Gαo is an essential requirement for the display of male-male territorial aggression as well as maternal aggression in mice. Finally, we show that Gαo-dependent maternal aggression can be induced by major urinary proteins. These cellular and behavioral phenotypes identify Gαo as the primary G-protein α-subunit mediating the detection of peptide and protein pheromones by sensory neurons of the VNO.

Authors
Chamero, P; Katsoulidou, V; Hendrix, P; Bufe, B; Roberts, R; Matsunami, H; Abramowitz, J; Birnbaumer, L; Zufall, F; Leinders-Zufall, T
MLA Citation
Chamero, P, Katsoulidou, V, Hendrix, P, Bufe, B, Roberts, R, Matsunami, H, Abramowitz, J, Birnbaumer, L, Zufall, F, and Leinders-Zufall, T. "G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice." Proc Natl Acad Sci U S A 108.31 (August 2, 2011): 12898-12903.
PMID
21768373
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
31
Publish Date
2011
Start Page
12898
End Page
12903
DOI
10.1073/pnas.1107770108

Functional Expression of Odorant Receptor In Vitro

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Functional Expression of Odorant Receptor In Vitro." IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 47 (June 2011): S12-S12.
Source
wos-lite
Published In
In Vitro Cellular & Developmental Biology - Animal
Volume
47
Publish Date
2011
Start Page
S12
End Page
S12

Assaying surface expression of chemosensory receptors in heterologous cells.

The vivid world of odors is recognized by the sense of olfaction. Olfaction in mice is mediated by a repertoire of about 1200 G Protein Coupled Receptors (GPCRs) that are postulated to bind volatile odorant molecules and converting the extracellular signal into an intracellular signal by coupling with G protein Gαolf. Binding of the odorants to the receptors is thought to follow a combinatorial rule, that is, one odorant may bind several receptors and one receptor may bind several odorants to varying degrees. Biochemical, signaling and ligand binding studies have been conveniently carried out for most GPCRs using heterologous cells. However use of heterologous cells for study of odorant receptors, was precluded for a long time since on transfection they failed to export to the surface. Saito et al have demonstrated single membrane pass Receptor Transporting Protein (RTP) family chaperones show enhanced expression in the olfactory sensory neurons and act as chaperones to traffic odorant receptors to the surface in heterologous cells, when co transfected together. To carry out biochemical assays for receptors using heterologous cells, one must first determine if the receptor shows robust surface expression in the cell line. This can be assayed by overexpressing the receptors with the chaperone RTP1S followed by live cell staining to fluorescently label the extracellular domain or a tag in the extracellular domain exclusively. Here we demonstrate a protocol to carry out live cell staining that can be used to detect odorant receptors on the surface of HEK293T cells conveniently. In addition, it may also be used to assay for surface expression of other chemosensory receptors or GPCRs.

Authors
Dey, S; Zhan, S; Matsunami, H
MLA Citation
Dey, S, Zhan, S, and Matsunami, H. "Assaying surface expression of chemosensory receptors in heterologous cells. (Published online)" J Vis Exp 48 (February 23, 2011).
PMID
21403623
Source
pubmed
Published In
Journal of Visualized Experiments
Issue
48
Publish Date
2011
DOI
10.3791/2405

Activation state of the M3 muscarinic acetylcholine receptor modulates mammalian odorant receptor signaling.

A diverse repertoire of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) enables cells to sense their environment. Mammalian olfaction requires the activation of odorant receptors (ORs), the largest family of GPCRs; however, whether ORs functionally interact with other families of GPCRs is unclear. We show that the interaction of ORs with the type 3 muscarinic acetylcholine receptor (M3-R), which is found in olfactory sensory neurons (OSNs), modulated OR responses to cognate odorants. In human embryonic kidney-293T cells, ORs and the M3-R physically interacted, and the M3-R increased the potency and efficacy of odorant-elicited responses of several ORs. Selective M3-R antagonists attenuated odorant-dependent activation of OSNs, and, when the M3-R and ORs were expressed in transfected cells, OR activation was enhanced by muscarinic agonists and inhibited by muscarinic antagonists. Furthermore, M3-R-dependent potentiation of OR signaling synergized with that of receptor transporting protein 1S (RTP1S), an accessory factor required for the efficient membrane targeting of ORs. However, the M3-R did not enhance the abundance of ORs at the cell surface, suggesting that the M3-R acted through a distinct mechanism independent of RTP1S. Finally, the activation of ORs by cognate odorants transactivated the M3-R in the absence of its agonist. The crosstalk between ORs and the M3-R suggests that the functional coupling of ORs and the M3-R is required for robust OR activation.

Authors
Li, YR; Matsunami, H
MLA Citation
Li, YR, and Matsunami, H. "Activation state of the M3 muscarinic acetylcholine receptor modulates mammalian odorant receptor signaling. (Published online)" Sci Signal 4.155 (January 11, 2011): ra1-.
PMID
21224444
Source
pubmed
Published In
Science Signaling
Volume
4
Issue
155
Publish Date
2011
Start Page
ra1
DOI
10.1126/scisignal.2001230

Common promoter elements in odorant and vomeronasal receptor genes.

In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms underlying OR and VR gene expression remain unclear. Here we investigated if OR and V1R genes share common sequences in their promoter regions.We conducted a comparative analysis of promoter regions of 39 mouse V1R genes and found motifs that are common to a large number of promoters. We then searched mouse OR promoter regions for motifs that resemble the ones found in the V1R promoters. We identified motifs that are present in both the V1R and OR promoter regions. Some of these motifs correspond to the known O/E like binding sites while others resemble binding sites for transcriptional repressors. We show that one of these motifs specifically interacts with proteins extracted from both nuclei from olfactory and vomeronasal neurons. Our study is the first to identify motifs that resemble binding sites for repressors in the promoters of OR and V1R genes. Analysis of these motifs and of the proteins that bind to these motifs should reveal important aspects of the mechanisms of OR/V1R gene regulation.

Authors
Michaloski, JS; Galante, PAF; Nagai, MH; Armelin-Correa, L; Chien, M-S; Matsunami, H; Malnic, B
MLA Citation
Michaloski, JS, Galante, PAF, Nagai, MH, Armelin-Correa, L, Chien, M-S, Matsunami, H, and Malnic, B. "Common promoter elements in odorant and vomeronasal receptor genes." PLoS One 6.12 (2011): e29065-.
PMID
22216168
Source
pubmed
Published In
PloS one
Volume
6
Issue
12
Publish Date
2011
Start Page
e29065
DOI
10.1371/journal.pone.0029065

Sour taste responses in mice lacking PKD channels.

BACKGROUND: The polycystic kidney disease-like ion channel PKD2L1 and its associated partner PKD1L3 are potential candidates for sour taste receptors. PKD2L1 is expressed in type III taste cells that respond to sour stimuli and genetic elimination of cells expressing PKD2L1 substantially reduces chorda tympani nerve responses to sour taste stimuli. However, the contribution of PKD2L1 and PKD1L3 to sour taste responses remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We made mice lacking PKD2L1 and/or PKD1L3 gene and investigated whole nerve responses to taste stimuli in the chorda tympani or the glossopharyngeal nerve and taste responses in type III taste cells. In mice lacking PKD2L1 gene, chorda tympani nerve responses to sour, but not sweet, salty, bitter, and umami tastants were reduced by 25-45% compared with those in wild type mice. In contrast, chorda tympani nerve responses in PKD1L3 knock-out mice and glossopharyngeal nerve responses in single- and double-knock-out mice were similar to those in wild type mice. Sour taste responses of type III fungiform taste cells (GAD67-expressing taste cells) were also reduced by 25-45% by elimination of PKD2L1. CONCLUSIONS/SIGNIFICANCE: These findings suggest that PKD2L1 partly contributes to sour taste responses in mice and that receptors other than PKDs would be involved in sour detection.

Authors
Horio, N; Yoshida, R; Yasumatsu, K; Yanagawa, Y; Ishimaru, Y; Matsunami, H; Ninomiya, Y
MLA Citation
Horio, N, Yoshida, R, Yasumatsu, K, Yanagawa, Y, Ishimaru, Y, Matsunami, H, and Ninomiya, Y. "Sour taste responses in mice lacking PKD channels." PLoS One 6.5 (2011): e20007-.
PMID
21625513
Source
pubmed
Published In
PloS one
Volume
6
Issue
5
Publish Date
2011
Start Page
e20007
DOI
10.1371/journal.pone.0020007

Assaying surface expression of chemosensory receptors in heterologous cells.

The vivid world of odors is recognized by the sense of olfaction. Olfaction in mice is mediated by a repertoire of about 1200 G Protein Coupled Receptors (GPCRs) that are postulated to bind volatile odorant molecules and converting the extracellular signal into an intracellular signal by coupling with G protein Gαolf. Binding of the odorants to the receptors is thought to follow a combinatorial rule, that is, one odorant may bind several receptors and one receptor may bind several odorants to varying degrees. Biochemical, signaling and ligand binding studies have been conveniently carried out for most GPCRs using heterologous cells. However use of heterologous cells for study of odorant receptors, was precluded for a long time since on transfection they failed to export to the surface. Saito et al have demonstrated single membrane pass Receptor Transporting Protein (RTP) family chaperones show enhanced expression in the olfactory sensory neurons and act as chaperones to traffic odorant receptors to the surface in heterologous cells, when co transfected together. To carry out biochemical assays for receptors using heterologous cells, one must first determine if the receptor shows robust surface expression in the cell line. This can be assayed by overexpressing the receptors with the chaperone RTP1S followed by live cell staining to fluorescently label the extracellular domain or a tag in the extracellular domain exclusively. Here we demonstrate a protocol to carry out live cell staining that can be used to detect odorant receptors on the surface of HEK293T cells conveniently. In addition, it may also be used to assay for surface expression of other chemosensory receptors or GPCRs.

Authors
Dey, S; Zhan, S; Matsunami, H
MLA Citation
Dey, S, Zhan, S, and Matsunami, H. "Assaying surface expression of chemosensory receptors in heterologous cells." Journal of visualized experiments : JoVE 48 (2011).
Source
scival
Published In
Journal of Visualized Experiments
Issue
48
Publish Date
2011
DOI
10.3791/2405

Interaction between PKD1L3 and PKD2L1 through their transmembrane domains is required for localization of PKD2L1 at taste pores in taste cells of circumvallate and foliate papillae.

The polycystic kidney disease 1-like 3 (PKD1L3) and polycystic kidney disease 2-like 1 (PKD2L1) proteins have been proposed to form heteromers that function as sour taste receptors in mammals. Here, we show that PKD1L3 and PKD2L1 interact through their transmembrane domains, and not through the coiled-coil domain, by coimmunoprecipitation experiments using a series of deletion mutants. Deletion mutants lacking the critical interaction region were not transported to the cell surface and remained in the cytoplasm, whereas PKD1L3 and PKD2L1 proteins were expressed at the cell surface when both are transfected. Calcium imaging analysis revealed that neither the coiled-coil domain nor the EF-hand domain located in the C-terminal cytoplasmic tail of PKD2L1 was required for response on stimulation with an acidic solution. Finally, PKD2L1 did not localize to the taste pore but was distributed throughout the cytoplasm in taste cells of circumvallate and foliate papillae in PKD1L3(-/-) mice, whereas it localized to the taste pore in wild-type mice. Collectively, these results suggest that the interaction between PKD1L3 and PKD2L1 through their transmembrane domains is essential for proper trafficking of the channels to the cell surface in taste cells of circumvallate and foliate papillae and in cultured cells.

Authors
Ishimaru, Y; Katano, Y; Yamamoto, K; Akiba, M; Misaka, T; Roberts, RW; Asakura, T; Matsunami, H; Abe, K
MLA Citation
Ishimaru, Y, Katano, Y, Yamamoto, K, Akiba, M, Misaka, T, Roberts, RW, Asakura, T, Matsunami, H, and Abe, K. "Interaction between PKD1L3 and PKD2L1 through their transmembrane domains is required for localization of PKD2L1 at taste pores in taste cells of circumvallate and foliate papillae." FASEB J 24.10 (October 2010): 4058-4067.
PMID
20538909
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
24
Issue
10
Publish Date
2010
Start Page
4058
End Page
4067
DOI
10.1096/fj.10-162925

PKD2L1 is associated with the sour taste transduction

Authors
Horio, N; Yoshida, R; Yasumatsu, K; Yanagawa, Y; Ishimaru, Y; Matsunami, H
MLA Citation
Horio, N, Yoshida, R, Yasumatsu, K, Yanagawa, Y, Ishimaru, Y, and Matsunami, H. "PKD2L1 is associated with the sour taste transduction." NEUROSCIENCE RESEARCH 68 (2010): E385-E385.
Source
wos-lite
Published In
Neuroscience Research
Volume
68
Publish Date
2010
Start Page
E385
End Page
E385
DOI
10.1016/j.neures.2010.07.1703

Dynamic functional evolution of an odorant receptor for sex-steroid-derived odors in primates.

Odorant receptors are among the fastest evolving genes in animals. However, little is known about the functional changes of individual odorant receptors during evolution. We have recently demonstrated a link between the in vitro function of a human odorant receptor, OR7D4, and in vivo olfactory perception of 2 steroidal ligands--androstenone and androstadienone--chemicals that are shown to affect physiological responses in humans. In this study, we analyzed the in vitro function of OR7D4 in primate evolution. Orthologs of OR7D4 were cloned from different primate species. Ancestral reconstruction allowed us to reconstitute additional putative OR7D4 orthologs in hypothetical ancestral species. Functional analysis of these orthologs showed an extremely diverse range of OR7D4 responses to the ligands in various primate species. Functional analysis of the nonsynonymous changes in the Old World Monkey and Great Ape lineages revealed a number of sites causing increases or decreases in sensitivity. We found that the majority of the functionally important residues in OR7D4 were not predicted by the maximum likelihood analysis detecting positive Darwinian selection.

Authors
Zhuang, H; Chien, M-S; Matsunami, H
MLA Citation
Zhuang, H, Chien, M-S, and Matsunami, H. "Dynamic functional evolution of an odorant receptor for sex-steroid-derived odors in primates." Proceedings of the National Academy of Sciences of the United States of America 106.50 (December 2, 2009): 21247-21251.
PMID
19955411
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
50
Publish Date
2009
Start Page
21247
End Page
21251
DOI
10.1073/pnas.0808378106

SR1, a mouse odorant receptor with an unusually broad response profile.

The current consensus model in mammalian olfaction is that the detection of millions of odorants requires a large number of odorant receptors (ORs) and that each OR interacts selectively with a small subset of odorants, which are typically related in structure. Here, we report the odorant response properties of an OR that deviates from this model: SR1, a mouse OR that is abundantly expressed in sensory neurons of the septal organ and also of the main olfactory epithelium. Patch-clamp recordings reveal that olfactory sensory neurons (OSNs) that express SR1 respond to many, structurally unrelated odorants, and over a wide concentration range. Most OSNs expressing a gene-targeted SR1 locus that lacks the SR1 coding sequence do not show this broad responsiveness. Gene transfer in the heterologous expression system Hana3A confirms the broad response profile of SR1. There may be other mouse ORs with such broad response profiles.

Authors
Grosmaitre, X; Fuss, SH; Lee, AC; Adipietro, KA; Matsunami, H; Mombaerts, P; Ma, M
MLA Citation
Grosmaitre, X, Fuss, SH, Lee, AC, Adipietro, KA, Matsunami, H, Mombaerts, P, and Ma, M. "SR1, a mouse odorant receptor with an unusually broad response profile." J Neurosci 29.46 (November 18, 2009): 14545-14552.
PMID
19923288
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
29
Issue
46
Publish Date
2009
Start Page
14545
End Page
14552
DOI
10.1523/JNEUROSCI.2752-09.2009

Positive Selection Shapes the Function of an Odorant Receptor for Sex-Steroid Derived Odors in Primates

Authors
Zhuang, H; Chien, M; Matsunami, H
MLA Citation
Zhuang, H, Chien, M, and Matsunami, H. "Positive Selection Shapes the Function of an Odorant Receptor for Sex-Steroid Derived Odors in Primates." September 2009.
Source
wos-lite
Published In
Chemical Senses
Volume
34
Issue
7
Publish Date
2009
Start Page
A10
End Page
A10

Taste perception: how sweet it is (to be transcribed by you).

In mammals, sweet taste is mediated largely by a single receptor. New work shows that polymorphisms in the promoter region of one subunit contribute to variation in sweet perception in the human population.

Authors
Mainland, JD; Matsunami, H
MLA Citation
Mainland, JD, and Matsunami, H. "Taste perception: how sweet it is (to be transcribed by you)." Curr Biol 19.15 (August 11, 2009): R655-R656. (Review)
PMID
19674550
Source
pubmed
Published In
Current Biology
Volume
19
Issue
15
Publish Date
2009
Start Page
R655
End Page
R656
DOI
10.1016/j.cub.2009.06.050

Chemoreception scientists gather under the Florida sun: The 31st Annual Association for Chemoreception Sciences meeting.

The 31st Annual Association for Chemoreception Sciences (AChemS) met in Sarasota, Florida April 22-26, 2009, attracting approximately 600 registrants and nearly 400 abstracts. In addition to poster and platform presentations, the program offered symposia, special lectures, and various National Institutes of Health (NIH)-sponsored workshops, including one on computational approaches to olfaction.

Authors
Wilson, DA; Baker, H; Brunjes, P; Gilbertson, TA; Hermer, L; Hill, DL; Matsunami, H; Meredith, M; Mistretta, CM; Smeets, MAM; Stowers, L; Zhuang, H
MLA Citation
Wilson, DA, Baker, H, Brunjes, P, Gilbertson, TA, Hermer, L, Hill, DL, Matsunami, H, Meredith, M, Mistretta, CM, Smeets, MAM, Stowers, L, and Zhuang, H. "Chemoreception scientists gather under the Florida sun: The 31st Annual Association for Chemoreception Sciences meeting." Ann N Y Acad Sci 1170 Suppl 1 (August 2009): 1-11.
PMID
19712224
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1170 Suppl 1
Publish Date
2009
Start Page
1
End Page
11
DOI
10.1111/j.1749-6632.2009.05047.x

Trafficking of mammalian chemosensory receptors by receptor-transporting proteins.

Although mammalian odorant receptors (ORs) were identified more than 15 years ago, we still do not understand how odorant molecules interact with ORs at a molecular level. Previous studies of mammalian ORs have tested few ORs against many odorants. Some fundamental properties of the olfactory system, however, require investigation of a wide panel of diverse ORs with many chemically diverse odorants. Previously, we identified OR accessory proteins, receptor-transporting protein (RTP) 1 and RTP2. They are expressed specifically in olfactory neurons, are associated with OR proteins, and facilitate the OR trafficking to the plasma membrane when coexpressed in mammalian cell lines. With this approach, high-throughput screening using a large repertoire of mammalian ORs is now possible. The activation profiles can be used to develop a predictive model relating physicochemical odorant properties, receptor sequences, and their interactions, enabling us to predict a tested receptor's response to a novel odorant and a novel receptor's response to a tested odorant. Doing so will provide a basis for understanding how structurally diverse odorant molecules activate the mammalian OR repertoire. Similarly, two families of vomeronasal receptors, V1Rs and V2Rs, are also notoriously difficult to functionally express in heterologous cells. However, coexpression of the RTP family members with V1Rs or V2Rs does not seem to facilitate trafficking of the receptor proteins. This finding suggests that the vomeronasal organ has a unique biosynthetic pathway for membrane proteins.

Authors
Matsunami, H; Mainland, JD; Dey, S
MLA Citation
Matsunami, H, Mainland, JD, and Dey, S. "Trafficking of mammalian chemosensory receptors by receptor-transporting proteins." Ann N Y Acad Sci 1170 (July 2009): 153-156.
PMID
19686127
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1170
Publish Date
2009
Start Page
153
End Page
156
DOI
10.1111/j.1749-6632.2009.03888.x

Odor coding by a Mammalian receptor repertoire.

Deciphering olfactory encoding requires a thorough description of the ligands that activate each odorant receptor (OR). In mammalian systems, however, ligands are known for fewer than 50 of more than 1400 human and mouse ORs, greatly limiting our understanding of olfactory coding. We performed high-throughput screening of 93 odorants against 464 ORs expressed in heterologous cells and identified agonists for 52 mouse and 10 human ORs. We used the resulting interaction profiles to develop a predictive model relating physicochemical odorant properties, OR sequences, and their interactions. Our results provide a basis for translating odorants into receptor neuron responses and for unraveling mammalian odor coding.

Authors
Saito, H; Chi, Q; Zhuang, H; Matsunami, H; Mainland, JD
MLA Citation
Saito, H, Chi, Q, Zhuang, H, Matsunami, H, and Mainland, JD. "Odor coding by a Mammalian receptor repertoire. (Published online)" Sci Signal 2.60 (March 3, 2009): ra9-.
PMID
19261596
Source
pubmed
Published In
Science Signaling
Volume
2
Issue
60
Publish Date
2009
Start Page
ra9
DOI
10.1126/scisignal.2000016

Transient receptor potential (TRP) channels and taste sensation.

Humans have 5 basic taste sensations: sweet, bitter, sour, salty, and umami (taste of 1-amino acids). Among 33 genes related to transient receptor potential (TRP) channels, 3--including TRP-melastatin 5 (TRPM5), polycystic kidney disease-1-like 3 (PKD1L3), and polycystic kidney disease-2-like 1 (PKD2L1)--are specifically and abundantly expressed in taste receptor cells. TRP-melastatin 5 is co-expressed with taste receptors T1Rs and T2Rs, and functions as a common downstream component in sweet, bitter, and umami taste signal transduction. In contrast, polycystic kidney disease-1-like 3 and polycystic kidney disease-2-like 1 are co-expressed in distinct subsets of taste receptor cells not expressing TRP-melastatin 5. In the heterologous expression system, cells expressing both polycystic kidney disease-1-like 3 and polycystic kidney disease-2-like 1 responded to sour stimuli, showing a unique "off-response" property. Genetic ablation of poly-cystic kidney disease-2-like 1-expressing cells resulted in elimination of gustatory nerve response to sour stimuli, indicating that cells expressing polycystic kidney disease-2-like 1 function as sour taste detectors. These results suggest that polycystic kidney disease-1-like 3/polycystic kidney disease-2-like 1 may play a significant role, possibly as taste receptors, in sour taste sensation.

Authors
Ishimaru, Y; Matsunami, H
MLA Citation
Ishimaru, Y, and Matsunami, H. "Transient receptor potential (TRP) channels and taste sensation." J Dent Res 88.3 (March 2009): 212-218. (Review)
PMID
19329452
Source
pubmed
Published In
Journal of Dental Research
Volume
88
Issue
3
Publish Date
2009
Start Page
212
End Page
218
DOI
10.1177/0022034508330212

Odorant Receptor Polymorphisms and Olfactory Perception

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Odorant Receptor Polymorphisms and Olfactory Perception." CHEMICAL SENSES 34.3 (March 2009): E27-E27.
Source
wos-lite
Published In
Chemical Senses
Volume
34
Issue
3
Publish Date
2009
Start Page
E27
End Page
E27

Guanylyl cyclase-D in the olfactory CO2 neurons is activated by bicarbonate.

Atmospheric CO(2) is an important environmental cue that regulates several types of animal behavior. In mice, CO(2) responses of the olfactory sensory neurons (OSNs) require the activity of carbonic anhydrase to catalyze the conversion of CO(2) to bicarbonate and the opening of cGMP-sensitive ion channels. However, it remains unknown how the enhancement of bicarbonate levels results in cGMP production. Here, we show that bicarbonate activates cGMP-producing ability of guanylyl cyclase-D (GC-D), a membrane GC exclusively expressed in the CO(2)-responsive OSNs, by directly acting on the intracellular cyclase domain of GC-D. Also, the molecular mechanism for GC-D activation is distinct from the commonly believed model of "release from repression" for other membrane GCs. Our results contribute to our understanding of the molecular mechanisms of CO(2) sensing and suggest diverse mechanisms of molecular activation among membrane GCs.

Authors
Sun, L; Wang, H; Hu, J; Han, J; Matsunami, H; Luo, M
MLA Citation
Sun, L, Wang, H, Hu, J, Han, J, Matsunami, H, and Luo, M. "Guanylyl cyclase-D in the olfactory CO2 neurons is activated by bicarbonate." Proc Natl Acad Sci U S A 106.6 (February 10, 2009): 2041-2046.
PMID
19181845
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
6
Publish Date
2009
Start Page
2041
End Page
2046
DOI
10.1073/pnas.0812220106

Trafficking of Mammalian Chemosensory Receptors by Receptor-transporting Proteins

Authors
Matsunami, H; Mainland, JD; Dey, S
MLA Citation
Matsunami, H, Mainland, JD, and Dey, S. "Trafficking of Mammalian Chemosensory Receptors by Receptor-transporting Proteins." 2009.
Source
wos-lite
Published In
Annals of the New York Academy of Sciences
Volume
1170
Publish Date
2009
Start Page
153
End Page
156
DOI
10.1111/i.1749-6632.2009.03888.x

Dynamic Functional Evolution of an Odorant Receptor for Sex-steroid Derived Odors in Primates

Authors
Zhuang, H; Chien, M; Matsunami, H
MLA Citation
Zhuang, H, Chien, M, and Matsunami, H. "Dynamic Functional Evolution of an Odorant Receptor for Sex-steroid Derived Odors in Primates." NEUROSCIENCE RESEARCH 65 (2009): S139-S139.
Source
wos-lite
Published In
Neuroscience Research
Volume
65
Publish Date
2009
Start Page
S139
End Page
S139
DOI
10.1016/j.neures.2009.09.690

Odor coding by a mammalian receptor repertoire

Authors
Saito, H; Chi, Q; Zhuang, H; Matsunami, H; Mainland, J
MLA Citation
Saito, H, Chi, Q, Zhuang, H, Matsunami, H, and Mainland, J. "Odor coding by a mammalian receptor repertoire." NEUROSCIENCE RESEARCH 65 (2009): S76-S76.
Source
wos-lite
Published In
Neuroscience Research
Volume
65
Publish Date
2009
Start Page
S76
End Page
S76
DOI
10.1016/j.neures.2009.09.277

Receptors, circuits, and behaviors: new directions in chemical senses.

The chemical senses, smell and taste, are the most poorly understood sensory modalities. In recent years, however, the field of chemosensation has benefited from new methods and technical innovations that have accelerated the rate of scientific progress. For example, enormous advances have been made in identifying olfactory and gustatory receptor genes and mapping their expression patterns. Genetic tools now permit us to monitor and control neural activity in vivo with unprecedented precision. New imaging techniques allow us to watch neural activity patterns unfold in real time. Finally, improved hardware and software enable multineuron electrophysiological recordings on an expanded scale. These innovations have enabled some fresh approaches to classic problems in chemosensation.

Authors
Katz, DB; Matsunami, H; Rinberg, D; Scott, K; Wachowiak, M; Wilson, RI
MLA Citation
Katz, DB, Matsunami, H, Rinberg, D, Scott, K, Wachowiak, M, and Wilson, RI. "Receptors, circuits, and behaviors: new directions in chemical senses." J Neurosci 28.46 (November 12, 2008): 11802-11805. (Review)
PMID
19005043
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
28
Issue
46
Publish Date
2008
Start Page
11802
End Page
11805
DOI
10.1523/JNEUROSCI.3613-08.2008

Functional Expression of Mammalian Odorant Receptors by RTP Family Members

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Functional Expression of Mammalian Odorant Receptors by RTP Family Members." CHEMICAL SENSES 33.8 (October 2008): S19-S19.
Source
wos-lite
Published In
Chemical Senses
Volume
33
Issue
8
Publish Date
2008
Start Page
S19
End Page
S19

Odor Coding by a Mammalian Receptor Repertoire

Authors
Mainland, JD; Saito, H; Chi, Q; Zhuang, H; Matsunami, H
MLA Citation
Mainland, JD, Saito, H, Chi, Q, Zhuang, H, and Matsunami, H. "Odor Coding by a Mammalian Receptor Repertoire." CHEMICAL SENSES 33.8 (October 2008): S1-S1.
Source
wos-lite
Published In
Chemical Senses
Volume
33
Issue
8
Publish Date
2008
Start Page
S1
End Page
S1

Positive Selection Shapes the Function of an Odorant Receptor for Sex-Steroid Derived Odors in Primates

Authors
Zhuang, H; Matsunami, H
MLA Citation
Zhuang, H, and Matsunami, H. "Positive Selection Shapes the Function of an Odorant Receptor for Sex-Steroid Derived Odors in Primates." CHEMICAL SENSES 33.8 (October 2008): S50-S50.
Source
wos-lite
Published In
Chemical Senses
Volume
33
Issue
8
Publish Date
2008
Start Page
S50
End Page
S50

A Putative Endoplasmic Reticulum Chaperone, Calreticulin 4, is Expressed in Mouse Vomeronasal Organ

Authors
Dey, S; Matsunami, H
MLA Citation
Dey, S, and Matsunami, H. "A Putative Endoplasmic Reticulum Chaperone, Calreticulin 4, is Expressed in Mouse Vomeronasal Organ." CHEMICAL SENSES 33.8 (October 2008): S92-S92.
Source
wos-lite
Published In
Chemical Senses
Volume
33
Issue
8
Publish Date
2008
Start Page
S92
End Page
S92

Off-response property of an acid-activated cation channel complex PKD1L3-PKD2L1.

Ligand-gated ion channels are important in sensory and synaptic transduction. The PKD1L3-PKD2L1 channel complex is a sour taste receptor candidate that is activated by acids. Here, we report that the proton-activated PKD1L3-PKD2L1 ion channels have the unique ability to be activated after the removal of an acid stimulus. We refer to this property as the off-response (previously described as a delayed response). Electrophysiological analyses show that acid-induced responses are observed only after the removal of an acid solution at less than pH 3.0. A small increase in pH is sufficient for PKD1L3-PKD2L1 channel activation, after exposure to an acid at pH 2.5. These results indicate that this channel is a new type of ion channel-designated as an 'off-channel'-which is activated during stimulus application but not gated open until the removal of the stimulus. The off-response property of PKD1L3-PKD2L1 channels might explain the physiological phenomena occurring during sour taste sensation.

Authors
Inada, H; Kawabata, F; Ishimaru, Y; Fushiki, T; Matsunami, H; Tominaga, M
MLA Citation
Inada, H, Kawabata, F, Ishimaru, Y, Fushiki, T, Matsunami, H, and Tominaga, M. "Off-response property of an acid-activated cation channel complex PKD1L3-PKD2L1." EMBO Rep 9.7 (July 2008): 690-697.
PMID
18535624
Source
pubmed
Published In
EMBO Reports
Volume
9
Issue
7
Publish Date
2008
Start Page
690
End Page
697
DOI
10.1038/embor.2008.89

The candidate sour taste receptor, PKD2L1, is expressed by type III taste cells in the mouse.

The transient receptor potential channel, PKD2L1, is reported to be a candidate receptor for sour taste based on molecular biological and functional studies. Here, we investigated the expression pattern of PKD2L1-immunoreactivity (IR) in taste buds of the mouse. PKD2L1-IR is present in a few elongate cells in each taste bud as reported previously. The PKD2L1-expressing cells are different from those expressing PLCbeta2, a marker of Type II cells. Likewise PKD2L1-immunoreactive taste cells do not express ecto-ATPase which marks Type I cells. The PKD2L1-positive cells are immunoreactive for neural cell adhesion molecule, serotonin, PGP-9.5 (ubiquitin carboxy-terminal transferase), and chromogranin A, all of which are present in Type III taste cells. At the ultrastructural level, PKD2L1-immunoreactive cells form synapses onto afferent nerve fibers, another feature of Type III taste cells. These results are consistent with the idea that different taste cells in each taste bud perform distinct functions. We suggest that Type III cells are necessary for transduction and/or transmission of information about "sour", but have little or no role in transmission of taste information of other taste qualities.

Authors
Kataoka, S; Yang, R; Ishimaru, Y; Matsunami, H; Sévigny, J; Kinnamon, JC; Finger, TE
MLA Citation
Kataoka, S, Yang, R, Ishimaru, Y, Matsunami, H, Sévigny, J, Kinnamon, JC, and Finger, TE. "The candidate sour taste receptor, PKD2L1, is expressed by type III taste cells in the mouse." Chem Senses 33.3 (March 2008): 243-254.
PMID
18156604
Source
pubmed
Published In
Chemical Senses
Volume
33
Issue
3
Publish Date
2008
Start Page
243
End Page
254
DOI
10.1093/chemse/bjm083

Evaluating cell-surface expression and measuring activation of mammalian odorant receptors in heterologous cells.

A fundamental question in olfaction is which odorant receptors (ORs) are activated by a given odorant. A major roadblock to investigating odorant-OR relationships in mammals has been the inability to express ORs in heterologous cells suitable for screening active ligands for ORs. The discovery of the receptor-transporting protein family has facilitated the effective cell-surface expression of ORs in heterologous cells. The establishment of a robust heterologous expression system for mammalian ORs facilitates the high-throughput 'deorphanization' of these receptors by matching them to their cognate ligands. This protocol details the method used for evaluating the cell-surface expression and measuring the functional activation of ORs of transiently expressed mammalian ORs in HEK293T cells. The stages of OR cell-surface expression include cell culture preparation, transfer of cells, transfection, immunocytochemistry or flow cytometry, odorant stimulation and luciferase assay. This protocol can be completed in a period of 3 d from the transfer of cells to cell-surface expression detection and/or measurement of functional activation.

Authors
Zhuang, H; Matsunami, H
MLA Citation
Zhuang, H, and Matsunami, H. "Evaluating cell-surface expression and measuring activation of mammalian odorant receptors in heterologous cells." Nat Protoc 3.9 (2008): 1402-1413.
PMID
18772867
Source
pubmed
Published In
Nature Protocols
Volume
3
Issue
9
Publish Date
2008
Start Page
1402
End Page
1413
DOI
10.1038/nprot.2008.120

Genetic variation in a human odorant receptor alters odour perception.

Human olfactory perception differs enormously between individuals, with large reported perceptual variations in the intensity and pleasantness of a given odour. For instance, androstenone (5alpha-androst-16-en-3-one), an odorous steroid derived from testosterone, is variously perceived by different individuals as offensive ("sweaty, urinous"), pleasant ("sweet, floral") or odourless. Similar variation in odour perception has been observed for several other odours. The mechanistic basis of variation in odour perception between individuals is unknown. We investigated whether genetic variation in human odorant receptor genes accounts in part for variation in odour perception between individuals. Here we show that a human odorant receptor, OR7D4, is selectively activated in vitro by androstenone and the related odorous steroid androstadienone (androsta-4,16-dien-3-one) and does not respond to a panel of 64 other odours and two solvents. A common variant of this receptor (OR7D4 WM) contains two non-synonymous single nucleotide polymorphisms (SNPs), resulting in two amino acid substitutions (R88W, T133M; hence 'RT') that severely impair function in vitro. Human subjects with RT/WM or WM/WM genotypes as a group were less sensitive to androstenone and androstadienone and found both odours less unpleasant than the RT/RT group. Genotypic variation in OR7D4 accounts for a significant proportion of the valence (pleasantness or unpleasantness) and intensity variance in perception of these steroidal odours. Our results demonstrate the first link between the function of a human odorant receptor in vitro and odour perception.

Authors
Keller, A; Zhuang, H; Chi, Q; Vosshall, LB; Matsunami, H
MLA Citation
Keller, A, Zhuang, H, Chi, Q, Vosshall, LB, and Matsunami, H. "Genetic variation in a human odorant receptor alters odour perception." Nature 449.7161 (September 27, 2007): 468-472.
PMID
17873857
Source
pubmed
Published In
Nature
Volume
449
Issue
7161
Publish Date
2007
Start Page
468
End Page
472
DOI
10.1038/nature06162

Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse.

Carbon dioxide (CO2) is an important environmental cue for many organisms but is odorless to humans. It remains unclear whether the mammalian olfactory system can detect CO2 at concentrations around the average atmospheric level (0.038%). We demonstrated the expression of carbonic anhydrase type II (CAII), an enzyme that catabolizes CO2, in a subset of mouse olfactory neurons that express guanylyl cyclase D (GC-D+ neurons) and project axons to necklace glomeruli in the olfactory bulb. Exposure to CO2 activated these GC-D+ neurons, and exposure of a mouse to CO2 activated bulbar neurons associated with necklace glomeruli. Behavioral tests revealed CO2 detection thresholds of approximately 0.066%, and this sensitive CO2 detection required CAII activity. We conclude that mice detect CO2 at near-atmospheric concentrations through the olfactory subsystem of GC-D+ neurons.

Authors
Hu, J; Zhong, C; Ding, C; Chi, Q; Walz, A; Mombaerts, P; Matsunami, H; Luo, M
MLA Citation
Hu, J, Zhong, C, Ding, C, Chi, Q, Walz, A, Mombaerts, P, Matsunami, H, and Luo, M. "Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse." Science 317.5840 (August 17, 2007): 953-957.
PMID
17702944
Source
pubmed
Published In
Science
Volume
317
Issue
5840
Publish Date
2007
Start Page
953
End Page
957
DOI
10.1126/science.1144233

Synergism of accessory factors in functional expression of mammalian odorant receptors.

The discovery of odorant receptors led to endeavors in matching them with their cognate ligands. Although it has been challenging to functionally express odorant receptors in heterologous cells, previous studies have linked efficient odorant receptor expression with N-terminal modifications and accessory proteins, including the receptor-transporting proteins (RTPs) and Ric8b. Here we have shown that a shorter form of RTP1, RTP1S, supports robust cell-surface and functional expression of representative odorant receptors. Using a combination of accessory proteins, including RTP1S, Ric8b, and G(alphaolf), a diverse set of untagged odorant receptors were successfully expressed heterologously due to the synergistic effects among the various accessory proteins. Furthermore, the addition of an N-terminal rhodopsin tag to the odorant receptors, along with the same set of accessory proteins, exhibits an additional level of synergism, inducing enhanced odorant receptor responses to odorants and thus defining a more efficient heterologous expression system. We then showed that the presence or absence of different N-terminal tags has little effect on the ligand specificity of odorant receptors, although the amount of receptor expressed can play a role in the ligand response profile. The accuracy of the odorant receptor heterologous expression system involving tagged odorant receptors and various accessory proteins promises success in high throughput de-orphaning of mammalian odorant receptors.

Authors
Zhuang, H; Matsunami, H
MLA Citation
Zhuang, H, and Matsunami, H. "Synergism of accessory factors in functional expression of mammalian odorant receptors." J Biol Chem 282.20 (May 18, 2007): 15284-15293.
PMID
17387175
Source
pubmed
Published In
The Journal of biological chemistry
Volume
282
Issue
20
Publish Date
2007
Start Page
15284
End Page
15293
DOI
10.1074/jbc.M700386200

Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor.

Animals use their gustatory systems to evaluate the nutritious value, toxicity, sodium content, and acidity of food. Although characterization of molecular identities that receive taste chemicals is essential, molecular receptors underlying sour taste sensation remain unclear. Here, we show that two transient receptor potential (TRP) channel members, PKD1L3 and PKD2L1, are coexpressed in a subset of taste receptor cells in specific taste areas. Cells expressing these molecules are distinct from taste cells having receptors for bitter, sweet, or umami tastants. The PKD2L1 proteins are accumulated at the taste pore region, where taste chemicals are detected. PKD1L3 and PKD2L1 proteins can interact with each other, and coexpression of the PKD1L3 and PKD2L1 is necessary for their functional cell surface expression. Finally, PKD1L3 and PKD2L1 are activated by various acids when coexpressed in heterologous cells but not by other classes of tastants. These results suggest that PKD1L3 and PKD2L1 heteromers may function as sour taste receptors.

Authors
Ishimaru, Y; Inada, H; Kubota, M; Zhuang, H; Tominaga, M; Matsunami, H
MLA Citation
Ishimaru, Y, Inada, H, Kubota, M, Zhuang, H, Tominaga, M, and Matsunami, H. "Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor." Proc Natl Acad Sci U S A 103.33 (August 15, 2006): 12569-12574.
PMID
16891422
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
33
Publish Date
2006
Start Page
12569
End Page
12574
DOI
10.1073/pnas.0602702103

Functional analysis of a mammalian odorant receptor subfamily.

Phylogenetic analysis groups mammalian odorant receptors into two broad classes and numerous subfamilies. These subfamilies are proposed to reflect functional organization. Testing this idea requires an assay allowing detailed functional characterization of odorant receptors. Here we show that a variety of Class I and Class II mouse odorant receptors can be functionally expressed in Xenopus laevis oocytes. Receptor constructs included the N-terminal 20 residues of human rhodopsin and were co-expressed with Galphaolf and the cystic fibrosis transmembrane regulator to allow electrophysiological measurement of receptor responses. For most mouse odorant receptors tested, these conditions were sufficient for functional expression. Co-expression of accessory proteins was required to allow functional surface expression of some mouse odorant receptors. We used this assay to examine the receptive ranges of all members of the mouse odorant receptor 42 (MOR42) subfamily. MOR42-1 responded to dicarboxylic acids, preferring a 10-12 carbon chain length. MOR42-2 responded to monocarboxylic acids (7-10 carbons). MOR42-3 responded to dicarboxylic acids (8-10 carbons) and monocarboxylic acids (10-12 carbons). Thus, the receptive range of each receptor was unique. However, overlap between the individual receptive ranges suggests that the members of this subfamily form one contiguous subfamily receptive range, suggesting that odorant receptor subfamilies do constitute functional units.

Authors
Abaffy, T; Matsunami, H; Luetje, CW
MLA Citation
Abaffy, T, Matsunami, H, and Luetje, CW. "Functional analysis of a mammalian odorant receptor subfamily." J Neurochem 97.5 (June 2006): 1506-1518.
PMID
16606354
Source
pubmed
Published In
Journal of Neurochemistry
Volume
97
Issue
5
Publish Date
2006
Start Page
1506
End Page
1518
DOI
10.1111/j.1471-4159.2006.03859.x

The functional properties of mammalian odorant receptors

Authors
Saito, H; Chi, Q; Zhuang, H; Matsunami, H
MLA Citation
Saito, H, Chi, Q, Zhuang, H, and Matsunami, H. "The functional properties of mammalian odorant receptors." June 2006.
Source
wos-lite
Published In
Chemical Senses
Volume
31
Issue
5
Publish Date
2006
Start Page
A65
End Page
A65

Exploring the molecular receptive ranges of mammalian odorant receptors

Authors
Repicky, SE; Matsunami, H; Luetje, CW
MLA Citation
Repicky, SE, Matsunami, H, and Luetje, CW. "Exploring the molecular receptive ranges of mammalian odorant receptors." June 2006.
Source
wos-lite
Published In
Chemical Senses
Volume
31
Issue
5
Publish Date
2006
Start Page
A97
End Page
A97

Deorphanizing'' mammalian odorant receptors

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Deorphanizing'' mammalian odorant receptors." June 2006.
Source
wos-lite
Published In
Chemical Senses
Volume
31
Issue
5
Publish Date
2006
Start Page
A3
End Page
A3

Functional analysis of the mouse odorant receptor MOR42 subfamily

Authors
Abaffy, T; Matsunami, H; Luetje, C
MLA Citation
Abaffy, T, Matsunami, H, and Luetje, C. "Functional analysis of the mouse odorant receptor MOR42 subfamily." June 2006.
Source
wos-lite
Published In
Chemical Senses
Volume
31
Issue
5
Publish Date
2006
Start Page
A96
End Page
A97

Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations.

Cerebral cavernous malformations are vascular defects of the central nervous system consisting of clusters of dilated vessels that are subject to frequent hemorrhaging. The genes mutated in three forms of autosomal dominant cerebral cavernous malformations have been cloned, but it remains unclear which cell type is ultimately responsible for the lesion. In this article we describe mice with a gene trap insertion in the Ccm2 gene. Consistent with the human phenotype, heterozygous animals develop cerebral vascular malformations, although penetrance is low. Beta-galactosidase activity in heterozygous brain and in situ hybridization in wild-type brain revealed Ccm2 expression in neurons and choroid plexus but not in vascular endothelium of small vessels in the brain. The expression pattern of Ccm2 is similar to that of the Ccm1 gene and its interacting protein ICAP1 (Itgb1bp1). These data suggest that cerebral cavernous malformations arise as a result of defects in the neural parenchyma surrounding the vascular endothelial cells in the brain.

Authors
Plummer, NW; Squire, TL; Srinivasan, S; Huang, E; Zawistowski, JS; Matsunami, H; Hale, LP; Marchuk, DA
MLA Citation
Plummer, NW, Squire, TL, Srinivasan, S, Huang, E, Zawistowski, JS, Matsunami, H, Hale, LP, and Marchuk, DA. "Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations." Mamm Genome 17.2 (February 2006): 119-128.
PMID
16465592
Source
pubmed
Published In
Mammalian Genome
Volume
17
Issue
2
Publish Date
2006
Start Page
119
End Page
128
DOI
10.1007/s00335-005-0098-8

Functional expression of Mammalian odorant receptors.

Authors
Matsunami, H
MLA Citation
Matsunami, H. "Functional expression of Mammalian odorant receptors." Chem Senses 30 Suppl 1 (January 2005): i95-i96. (Review)
PMID
15738214
Source
pubmed
Published In
Chemical Senses
Volume
30 Suppl 1
Publish Date
2005
Start Page
i95
End Page
i96
DOI
10.1093/chemse/bjh131

RTP family members induce functional expression of mammalian odorant receptors.

Transport of G protein-coupled receptors (GPCRs) to the cell surface membrane is critical in order for the receptors to recognize their ligands. However, mammalian GPCR odorant receptors (ORs), when heterologously expressed in cells, are poorly expressed on the cell surface. Here we show that the transmembrane proteins RTP1 and RTP2 promote functional cell surface expression of ORs expressed in HEK293T cells. Genes encoding these proteins are expressed specifically in olfactory neurons. These proteins are associated with OR proteins and enhance the OR responses to odorants. Similar although weaker effects were seen with a third protein, REEP1. These findings suggest that RTP1 and RTP2 in particular play significant roles in the translocation of ORs to the plasma membrane as well as in the functioning of ORs. We have used this approach to identify active odorant ligands for ORs, providing a platform for screening the chemical selectivity of the large OR family.

Authors
Saito, H; Kubota, M; Roberts, RW; Chi, Q; Matsunami, H
MLA Citation
Saito, H, Kubota, M, Roberts, RW, Chi, Q, and Matsunami, H. "RTP family members induce functional expression of mammalian odorant receptors." Cell 119.5 (November 24, 2004): 679-691.
PMID
15550249
Source
pubmed
Published In
Cell
Volume
119
Issue
5
Publish Date
2004
Start Page
679
End Page
691
DOI
10.1016/j.cell.2004.11.021

An imaging-based approach to identify ligands for olfactory receptors.

Odorant receptors (ORs) form one of the largest gene families in the genome. However, the vast majority are orphan receptors as the ligands that activate them remain unknown. Deorphaning approaches have generally focused on finding ligands for particular receptors expressed in homologous or heterologous cells; these attempts have met with only partial success. Here, we outline a conceptually different strategy in which we search for odorant receptors activated by a known odorant. Intrinsic signal imaging of the main olfactory bulb is first used to locate activated glomeruli in vivo, followed by retrograde tracing to label the sensory neurons in the olfactory epithelium projecting to the activated glomerulus. Subsequently, single cell RT-PCR is used to reveal the identity of the odorant receptors expressed in retrogradely labeled neurons. To demonstrate the applicability of this method, we searched for candidate ORs responding to the aldehyde odorant butanal. This method may be a useful tool to decipher specific ligand--OR interactions in the mouse olfactory bulb.

Authors
Mizrahi, A; Matsunami, H; Katz, LC
MLA Citation
Mizrahi, A, Matsunami, H, and Katz, LC. "An imaging-based approach to identify ligands for olfactory receptors." Neuropharmacology 47.5 (October 2004): 661-668.
PMID
15458837
Source
pubmed
Published In
Neuropharmacology
Volume
47
Issue
5
Publish Date
2004
Start Page
661
End Page
668
DOI
10.1016/j.neuropharm.2004.07.020

Taste perception: how to make a gourmet mouse.

Sugars and amino acids are mainly associated with desirable taste sensation. A new study using knockout mouse models shows that the detection of various sugars, artificial sweeteners and L-amino acids is exclusively mediated by taste cells that express one or pair-wise combinations of three G protein coupled receptors, T1R1, T1R2 and T1R3

Authors
Matsunami, H; Amrein, H
MLA Citation
Matsunami, H, and Amrein, H. "Taste perception: how to make a gourmet mouse." Curr Biol 14.3 (February 3, 2004): R118-R120. (Review)
PMID
14986650
Source
pubmed
Published In
Current Biology
Volume
14
Issue
3
Publish Date
2004
Start Page
R118
End Page
R120

Taste and pheromone perception in mammals and flies.

The olfactory systems of insects and mammals have analogous anatomical features and use similar molecular logic for olfactory coding. The molecular underpinnings of the chemosensory systems that detect taste and pheromone cues have only recently been characterized. Comparison of these systems in Drosophila and mouse uncovers clear differences and a few surprising similarities.

Authors
Matsunami, H; Amrein, H
MLA Citation
Matsunami, H, and Amrein, H. "Taste and pheromone perception in mammals and flies." Genome Biol 4.7 (2003): 220-. (Review)
PMID
12844351
Source
pubmed
Published In
Genome Biology
Volume
4
Issue
7
Publish Date
2003
Start Page
220
DOI
10.1186/gb-2003-4-7-220

Receptors for bitter and sweet taste.

The identification of two families of receptors, T1Rs and T2Rs, for sweet and bitter taste stimuli has opened the door to understanding some of the basic mechanisms underlying taste transduction in mammals. Studies of the functions of these receptors and their patterns of expression provide important information regarding the detection of structurally diverse taste compounds and the manner in which different taste qualities are encoded in the mouth.

Authors
Montmayeur, JP; Matsunami, H
MLA Citation
Montmayeur, JP, and Matsunami, H. "Receptors for bitter and sweet taste." Curr Opin Neurobiol 12.4 (August 2002): 366-371. (Review)
PMID
12139982
Source
pubmed
Published In
Current Opinion in Neurobiology
Volume
12
Issue
4
Publish Date
2002
Start Page
366
End Page
371

A candidate taste receptor gene near a sweet taste locus.

The mechanisms underlying sweet taste in mammals have been elusive. Although numerous studies have implicated G proteins in sweet taste detection, the expected G protein-coupled receptors have not been found. Here we describe a candidate taste receptor gene, T1r3, that is located at or near the mouse Sac locus, a genetic locus that controls the detection of certain sweet tastants. T1R3 differs in amino acid sequence in mouse strains with different Sac phenotypes ('tasters' versus 'nontasters'). In addition, a perfect correlation exists between two different T1r3 alleles and Sac phenotypes in recombinant inbred mouse strains. The T1r3 gene is expressed in a subset of taste cells in circumvallate, foliate and fungiform taste papillae. In circumvallate and foliate papillae, most T1r3-expressing cells also express a gene encoding a related receptor, T1R2, raising the possibility that these cells recognize more than one ligand, or that the two receptors function as heterodimers.

Authors
Montmayeur, JP; Liberles, SD; Matsunami, H; Buck, LB
MLA Citation
Montmayeur, JP, Liberles, SD, Matsunami, H, and Buck, LB. "A candidate taste receptor gene near a sweet taste locus." Nat Neurosci 4.5 (May 2001): 492-498.
PMID
11319557
Source
pubmed
Published In
Nature Neuroscience
Volume
4
Issue
5
Publish Date
2001
Start Page
492
End Page
498
DOI
10.1038/87440

A family of candidate taste receptors in human and mouse.

The gustatory system of mammals can sense four basic taste qualities, bitter, sweet, salty and sour, as well as umami, the taste of glutamate. Previous studies suggested that the detection of bitter and sweet tastants by taste receptor cells in the mouth is likely to involve G-protein-coupled receptors. Although two putative G-protein-coupled bitter/sweet taste receptors have been identified, the chemical diversity of bitter and sweet compounds leads one to expect that there is a larger number of different receptors. Here we report the identification of a family of candidate taste receptors (the TRBs) that are members of the G-protein-coupled receptor superfamily and that are specifically expressed by taste receptor cells. A cluster of genes encoding human TRBs is located adjacent to a Prp gene locus, which in mouse is tightly linked to the SOA genetic locus that is involved in detecting the bitter compound sucrose octaacetate. Another TRB gene is found on a human contig assigned to chromosome 5p15, the location of a genetic locus (PROP) that controls the detection of the bitter compound 6-n-propyl-2-thiouracil in humans.

Authors
Matsunami, H; Montmayeur, JP; Buck, LB
MLA Citation
Matsunami, H, Montmayeur, JP, and Buck, LB. "A family of candidate taste receptors in human and mouse." Nature 404.6778 (April 6, 2000): 601-604.
PMID
10766242
Source
pubmed
Published In
Nature
Volume
404
Issue
6778
Publish Date
2000
Start Page
601
End Page
604
DOI
10.1038/35007072

Involvement of R-cadherin in the early stage of glomerulogenesis.

The earliest commitment to the formation of glomeruli is recognizable in S-shaped bodies. Although cell-cell adhesion seems likely to play a crucial role in this process, how glomerular epithelial cells segregate from the other parts of the nephron is unknown. In this study, immunofluorescence microscopy and monoclonal antibodies specific for mouse R-, E-, P- and N-cadherins were used to examine which of these adhesion molecules are involved in glomerulogenesis of the mouse kidney. Weak R-cadherin staining was first found in the vesicle stage, becoming restricted to glomerular visceral epithelial cells (VEC) during the S-shaped body stage. The intensity of this staining became stronger in the capillary loop stage, whereas parietal epithelial cells (PEC) and tubular cells did not stain. In the maturing stage, VEC gradually lost their staining for R-cadherin. E-cadherin was detected in ureteric buds and the upper limb of S-shaped bodies. From the capillary loop to the maturing stage, anti-E-cadherin stained epithelial cells in all tubule segments, but no label was seen in VEC or PEC. P-cadherin was also stained in the ureteric buds and in the upper limb of S-shaped bodies. N-Cadherin was weakly stained in cells at the vesicle stage, but thereafter staining of N-cadherin was not detected at any stage of glomerular formation. Immunoelectron microscopy of differentiating VEC was performed using antibodies specific to alpha-catenin, which is associated with cadherin. Subsequently, immunogold particles identifying alpha-catenin were localized on junctions between primary processes of VEC. These findings indicate that R-cadherin is uniquely expressed in differentiating VEC, suggesting an important role in the early stages of glomerulogenesis.

Authors
Goto, S; Yaoita, E; Matsunami, H; Kondo, D; Yamamoto, T; Kawasaki, K; Arakawa, M; Kihara, I
MLA Citation
Goto, S, Yaoita, E, Matsunami, H, Kondo, D, Yamamoto, T, Kawasaki, K, Arakawa, M, and Kihara, I. "Involvement of R-cadherin in the early stage of glomerulogenesis." J Am Soc Nephrol 9.7 (July 1998): 1234-1241.
PMID
9644633
Source
pubmed
Published In
Journal of the American Society of Nephrology : JASN
Volume
9
Issue
7
Publish Date
1998
Start Page
1234
End Page
1241

Selective aggregation assays for embryonic brain cells and cell lines.

Authors
Nakagawa, S; Matsunami, H; Takeichi, M; Matsunami, H
MLA Citation
Nakagawa, S, Matsunami, H, Takeichi, M, and Matsunami, H. "Selective aggregation assays for embryonic brain cells and cell lines." Curr Top Dev Biol 36 (1998): 197-210. (Review)
PMID
9342529
Source
pubmed
Published In
Current topics in developmental biology
Volume
36
Publish Date
1998
Start Page
197
End Page
210

A multigene family encoding a diverse array of putative pheromone receptors in mammals.

The vomeronasal organ of mammals is an olfactory sensory structure that detects pheromones. It contains two subsets of sensory neurons that differentially express G alpha(o) and G alpha(i2). By comparing gene expression in single neurons, we identified a novel multigene family that codes for a diverse array of candidate pheromone receptors (VRs) expressed by the G alpha(o)+ subset. Different VRs are expressed by different neurons, but those neurons are interspersed, suggesting a distributed mode of sensory coding. Chromosome mapping experiments suggest an evolutionary connection between genes encoding VRs and receptors for volatile odorants. However, a dramatically different structure for VRs and the existence of variant VR mRNA forms indicate that there are diverse strategies to detect functionally distinct sensory stimuli.

Authors
Matsunami, H; Buck, LB
MLA Citation
Matsunami, H, and Buck, LB. "A multigene family encoding a diverse array of putative pheromone receptors in mammals." Cell 90.4 (August 22, 1997): 775-784.
PMID
9288756
Source
pubmed
Published In
Cell
Volume
90
Issue
4
Publish Date
1997
Start Page
775
End Page
784

Cadherin-6 expression transiently delineates specific rhombomeres, other neural tube subdivisions, and neural crest subpopulations in mouse embryos.

Mammalian cadherin-6 (K-cadherin, cad6) was originally identified by means of the polymerase chain reaction, but its biological functions have not yet been determined. We analyzed the expression pattern of the mouse homologue of this cadherin during development and found that it was transiently expressed in restricted rhombomeres and in other subdivisions of the neural plate and tube. In the midbrain and anterior hindbrain of E8.0-8.5 embryos, cad6 was expressed only in neural crest-generating regions. In contrast, in the posterior hindbrain and contiguous spinal cord of these embryos, cad6 occurred throughout the neural plate, forming a sharp anterior limit at the future rhombomere 4 and 5 boundary. Subsequently, this neural plate expression became confined to rhombomere 6, although most of the neural crest-generating areas remained positive throughout the body. Neural crest cells expressing cad6 migrated out of the neural tube, and subsequently accumulated mainly along peripheral nerves. We then studied the effect of Hoxa-1 mutation on the expression of cad6, as their expressions spatiotemporally overlapped with each other in the early posterior hindbrain. In E8.0-8.5 Hoxa-1 mutants, cad6 expression was suppressed in the region of rhombomeres 4 to 6, although that in the other regions was not essentially affected. At later stages, however, cad6-positive crest cells appeared and migrated out of rhombomeres 4 to 6, indicating that the suppression of cad6 expression was transient and restricted to early stages. Importantly, this effect of the Hoxa-1 mutation concurred with the timing of the expression of this gene. We also studied Hoxa-3 mutants, but found no effect of this mutation on the cad6 expression pattern. These findings suggest that cad6 may contribute to the formation of the segmental structure of the early brain through its ability to confer specific adhesiveness on cells and that Hoxa-1 may be required for early cad6 expression in the posterior hindbrain.

Authors
Inoue, T; Chisaka, O; Matsunami, H; Takeichi, M
MLA Citation
Inoue, T, Chisaka, O, Matsunami, H, and Takeichi, M. "Cadherin-6 expression transiently delineates specific rhombomeres, other neural tube subdivisions, and neural crest subpopulations in mouse embryos." Dev Biol 183.2 (March 15, 1997): 183-194.
PMID
9126293
Source
pubmed
Published In
Developmental Biology
Volume
183
Issue
2
Publish Date
1997
Start Page
183
End Page
194
DOI
10.1006/dbio.1996.8501

Developmental defects in mouse embryos lacking N-cadherin.

To investigate the functions of N-cadherin in vivo, we have mutated the gene encoding this adhesion protein in mice. Although N-cadherin is expressed at the time of gastrulation and neurulation, both neurulation and somitogenesis initiate apparently normally in homozygous mutant embryos. However, the resulting structures are often malformed. The somites of the mutant embryos are small, irregularly shaped, and less cohesive compared with those of their wild-type littermates, and the epithelial organization of the somites is partially disrupted. Undulation of the neural tube is also observed in the mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The mesodermal and endodermal cell layers of the yolk sac are separated in the mutants. The most dramatic cell adhesion defect is observed in the primitive heart; although myocardial tissue forms initially, the myocytes subsequently dissociate and the heart tube fails to develop normally. In vitro studies of cardiac myocytes derived from N-cadherin mutant embryos show that the cells can loosely aggregate and beat synchronously, demonstrating that electrical coupling can occur between N-cadherin-deficient cardiac myocytes. These results show that N-cadherin plays a critical role in early heart development as well as in other morphogenetic processes.

Authors
Radice, GL; Rayburn, H; Matsunami, H; Knudsen, KA; Takeichi, M; Hynes, RO
MLA Citation
Radice, GL, Rayburn, H, Matsunami, H, Knudsen, KA, Takeichi, M, and Hynes, RO. "Developmental defects in mouse embryos lacking N-cadherin." Dev Biol 181.1 (January 1, 1997): 64-78.
PMID
9015265
Source
pubmed
Published In
Developmental Biology
Volume
181
Issue
1
Publish Date
1997
Start Page
64
End Page
78
DOI
10.1006/dbio.1996.8443

Roles of cadherins in patterning of the developing brain.

Authors
Takeichi, M; Matsunami, H; Inoue, T; Kimura, Y; Suzuki, S; Tanaka, T
MLA Citation
Takeichi, M, Matsunami, H, Inoue, T, Kimura, Y, Suzuki, S, and Tanaka, T. "Roles of cadherins in patterning of the developing brain." Dev Neurosci 19.1 (1997): 86-87.
PMID
9078437
Source
pubmed
Published In
Developmental neuroscience
Volume
19
Issue
1
Publish Date
1997
Start Page
86
End Page
87

Expression of cadherin-11 delineates boundaries, neuromeres, and nuclei in the developing mouse brain.

Cadherin-11 (cad11 or OB-cadherin) was previously identified as a mesenchymal cell-cell adhesion molecule. Here we studied the expression of cad11 transcripts in developing brains derived from E11.5 to E16.5 mouse embryos. In the brains at these stages, cad11 was expressed in various patterns, which could be grouped into three categories. First, cad11 expression occurred along boundaries between certain brain subdivisions, including those between the ventral and dorsal thalamus and between the mesencephalon and metencephalon. At these boundaries, cad11-positive cells were localized in a narrow, columnar compartment of the neuroepithelium. Second, cad11 expression delineated particular neuromeric compartments at the ventricular zone of the neuroepithelium. A typical example of this pattern was observed in the hypothalamus. Third, cad11 was expressed in differentiating or differentiated brain nuclei. The former included the thalamus, epithalamus, and pretectum; the latter included the mammillary, red, trigeminal motor, facial motor, prepositus hypoglossal, and inferior olive nuclei, as well as the substantia nigra. Furthermore, developing nuclei and the superficial zone of the cerebellum expressed cad11, and the cortical plate of the developing cerebrum also did so. We compared the expression pattern of cad11 with that of R-cadherin in the diencephalon and found that each cadherin delineated a unique set of diencephalic subdivisions. These findings suggest that cad11-mediated specific cell-cell adhesion plays roles in segmentation or compartmentalization of the developing brain in various ways. We also discussed the possibility that cad11 might be involved in neuronal connections between specific nuclei.

Authors
Kimura, Y; Matsunami, H; Takeichi, M
MLA Citation
Kimura, Y, Matsunami, H, and Takeichi, M. "Expression of cadherin-11 delineates boundaries, neuromeres, and nuclei in the developing mouse brain." Dev Dyn 206.4 (August 1996): 455-462.
PMID
8853994
Source
pubmed
Published In
Developmental Dynamics
Volume
206
Issue
4
Publish Date
1996
Start Page
455
End Page
462
DOI
10.1002/(SICI)1097-0177(199608)206:4<455::AID-AJA11>3.0.CO;2-W

Fetal brain subdivisions defined by R- and E-cadherin expressions: evidence for the role of cadherin activity in region-specific, cell-cell adhesion.

We found that R-cadherin, a Ca2(+)-dependent cell--cell adhesion molecule, is expressed in restricted regions of the mouse fetal brain, as was found for E-cadherin previously. R-cadherin delineated a subset of alar domains within forebrain neuromeres and certain future nuclei, while E-cadherin was expressed in another distinctive pattern. When cells were collected from various local regions of the fetal brain, dissociated, and reaggregated under the conditions in which only cadherins are active for cell aggregation, R-cadherin-positive and -negative cells segregated from one another. Similar results were obtained for E-cadherin. Such segregation of cells was, however, suppressed when the cadherins were inactivated either by Ca2+ depletion or with blocking antibodies. These results suggest that cadherins confer region-specific adhesiveness on fetal brain cells and that this process may take part in brain segmentation.

Authors
Matsunami, H; Takeichi, M
MLA Citation
Matsunami, H, and Takeichi, M. "Fetal brain subdivisions defined by R- and E-cadherin expressions: evidence for the role of cadherin activity in region-specific, cell-cell adhesion." Dev Biol 172.2 (December 1995): 466-478.
PMID
8612964
Source
pubmed
Published In
Developmental Biology
Volume
172
Issue
2
Publish Date
1995
Start Page
466
End Page
478
DOI
10.1006/dbio.1995.8029

Cadherin-11 expressed in association with mesenchymal morphogenesis in the head, somite, and limb bud of early mouse embryos.

Cadherin-11 (cad-11) is a novel member of the cadherin family of cell adhesion molecules, having recently been identified by means of the polymerase chain reaction. To study the function and expression of this molecule, we cloned mouse, cad-11 cDNA. Transfection of L cells with cDNA led them to acquire a typical cadherin-dependent cell-cell adhesiveness, and the L cells expressing cad-11 did not coaggregate with L cells expressing E-, P-, N-, or R-cadherin when they were mixed, indicating that this novel cadherin has a homophilic binding specificity, as found for other cadherins. To determine the developmental expression pattern of this molecule, we performed in situ hybridization analysis on early mouse embryos. Cad-11 first appeared in mesodermal layers only in the head and tail regions at the mid-to-late primitive streak stages. In the head, this appearance was followed by strong expression in mesenchymal tissues including branchial arches. In the trunk, the paraxial mesoderm initially did not express cad-11. However, as the somites formed, they expressed cad-11, and this expression was strictly correlated with their initial condensation and segregation from the presomitic mesoderm. The cad-11 expression in the somites was eventually restricted to sclerotome cells. As the limb buds developed, cad-11 appeared in the distal portion of the limb mesenchyme, and, at later stages, its expression was most evident at the peripheral mesenchyme. Cad-11 was thus expressed by restricted populations of mesenchymal cells in early embryos, although it was also expressed in parts of the neural tube, such as the optic vesicle and dorsal midline, and in part of the otic vesicle. As a step to investigate the role of cad-11 in mesenchymal cell adhesion, we dissociated the limb bud mesenchyme into single cells, pelleted them, and cultured them as aggregates. In these cultures, cad-11-positive cells clearly sorted out of the negative cell population, suggesting that cad-11 might be involved in selective association of mesenchymal cells. For comparison, we studied the expression of N-cadherin and found that the expressions of these two cadherins were differential, and complementary in some tissues. These results suggest that cad-11 is involved in specific associations of subsets of mesenchymal cells and also of some neural cells during early embryogenesis.

Authors
Kimura, Y; Matsunami, H; Inoue, T; Shimamura, K; Uchida, N; Ueno, T; Miyazaki, T; Takeichi, M
MLA Citation
Kimura, Y, Matsunami, H, Inoue, T, Shimamura, K, Uchida, N, Ueno, T, Miyazaki, T, and Takeichi, M. "Cadherin-11 expressed in association with mesenchymal morphogenesis in the head, somite, and limb bud of early mouse embryos." Dev Biol 169.1 (May 1995): 347-358.
PMID
7750650
Source
pubmed
Published In
Developmental Biology
Volume
169
Issue
1
Publish Date
1995
Start Page
347
End Page
358
DOI
10.1006/dbio.1995.1149

Cell binding specificity of mouse R-cadherin and chromosomal mapping of the gene.

R-cadherin was originally identified as a chicken cadherin expressed by the retina. Here, we describe the identification of a mouse homologue of R-cadherin. We isolated mouse cDNAs encoding a cadherin with 94% identity in amino acid sequence to the chicken R-cadherin, and defined this molecule as mouse R-cadherin. L cells transfected with the mouse R-cadherin cDNA acquired a cadherin-mediated cell-cell adhesiveness as found for other cadherins. To examine the binding specificity of mouse R-cadherin, L cells expressing this cadherin (mRL) were mixed with L cells expressing chicken R-cadherin (cRL), mouse N-cadherin (mNL), mouse E-cadherin (mEL) and mouse P-cadherin (mPL). While mRL cells randomly intermixed with cRL cells, those cells aggregated separately from mEL or mPL cells. Mixing of mRL with mNL cells gave an intermediate result; that is, they formed both separate and chimeric aggregates, suggesting that R- and N-cadherin can interact with each other although each has a preference to bind to its own type. Similar properties were previously found for chicken R-cadherin. Thus, the cell binding specificity of R-cadherin is entirely conserved between the two species, suggesting a conserved role for this protein in morphogenesis. We also located the mouse R-cadherin gene to chromosome 2.

Authors
Matsunami, H; Miyatani, S; Inoue, T; Copeland, NG; Gilbert, DJ; Jenkins, NA; Takeichi, M
MLA Citation
Matsunami, H, Miyatani, S, Inoue, T, Copeland, NG, Gilbert, DJ, Jenkins, NA, and Takeichi, M. "Cell binding specificity of mouse R-cadherin and chromosomal mapping of the gene." J Cell Sci 106 ( Pt 1) (September 1993): 401-409.
PMID
8270638
Source
pubmed
Published In
Journal of cell science
Volume
106 ( Pt 1)
Publish Date
1993
Start Page
401
End Page
409
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