Abstract
The mammalian olfactory system detects chemicals sensed as odours as well as social cues that stimulate innate responses. Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose ∼1,000 members allow the discrimination of a myriad of odorants. Here we report the discovery of a second family of receptors in the mouse olfactory epithelium. Genes encoding these receptors, called ‘trace amine-associated receptors’ (TAARs), are present in human, mouse and fish. Like odorant receptors, individual mouse TAARs are expressed in unique subsets of neurons dispersed in the epithelium. Notably, at least three mouse TAARs recognize volatile amines found in urine: one detects a compound linked to stress, whereas the other two detect compounds enriched in male versus female urine—one of which is reportedly a pheromone. The evolutionary conservation of the TAAR family suggests a chemosensory function distinct from odorant receptors. Ligands identified for TAARs thus far suggest a function associated with the detection of social cues.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175–187 (1991)
Kandel, E. R., Schwartz, J. H. & Jessell, T. M. Principles of Neural Science (McGraw-Hill, New York, 2000)
Buck, L. B. The molecular architecture of odor and pheromone sensing in mammals. Cell 100, 611–618 (2000)
Shepherd, G. M., Chen, W. R. & Greer, C. A. in The Synaptic Organization of the Brain (ed. Shepherd, G. M.) 165–216 (Oxford Univ. Press, New York, 2004)
Malnic, B., Hirono, J., Sato, T. & Buck, L. B. Combinatorial receptor codes for odors. Cell 96, 713–723 (1999)
Ressler, K. J., Sullivan, S. L. & Buck, L. B. A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell 73, 597–609 (1993)
Vassar, R., Ngai, J. & Axel, R. Spatial segregation of odorant receptor expression in the mammalian olfactory epithelium. Cell 74, 309–318 (1993)
Zhang, X. & Firestein, S. The olfactory receptor gene superfamily of the mouse. Nature Neurosci. 5, 124–133 (2002)
Young, J. M. & Trask, B. J. The sense of smell: genomics of vertebrate odorant receptors. Hum. Mol. Genet. 11, 1153–1160 (2002)
Godfrey, P. A., Malnic, B. & Buck, L. B. The mouse olfactory receptor gene family. Proc. Natl Acad. Sci. USA 101, 2156–2161 (2004)
Meyer, M. R., Angele, A., Kremmer, E., Kaupp, U. B. & Muller, F. A cGMP-signaling pathway in a subset of olfactory sensory neurons. Proc. Natl Acad. Sci. USA 97, 10595–10600 (2000)
Jones, D. T. & Reed, R. R. Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science 244, 790–795 (1989)
Spehr, M. et al. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961–1970 (2006)
Halpern, M. & Martinez-Marcos, A. Structure and function of the vomeronasal system: an update. Prog. Neurobiol. 70, 245–318 (2003)
Restrepo, D., Arellano, J., Oliva, A. M., Schaefer, M. L. & Lin, W. Emerging views on the distinct but related roles of the main and accessory olfactory systems in responsiveness to chemosensory signals in mice. Horm. Behav. 46, 247–256 (2004)
Boehm, U., Zou, Z. & Buck, L. B. Feedback loops link odor and pheromone signaling with reproduction. Cell 123, 683–695 (2005)
Yoon, H., Enquist, L. W. & Dulac, C. Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell 123, 669–682 (2005)
Fiering, S. N. et al. Improved FACS-Gal: flow cytometric analysis and sorting of viable eukaryotic cells expressing reporter gene constructs. Cytometry 12, 291–301 (1991)
Vassilatis, D. K. et al. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl Acad. Sci. USA 100, 4903–4908 (2003)
Lewin, A. H. Receptors of mammalian trace amines. AAPS J. 8, E138–E145 (2006)
Lindemann, L. & Hoener, M. C. A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol. Sci. 26, 274–281 (2005)
Gloriam, D. E. et al. The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish. Mol. Phylogenet. Evol. 35, 470–482 (2005)
Borowsky, B. et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc. Natl Acad. Sci. USA 98, 8966–8971 (2001)
Vanti, W. B. et al. Discovery of a null mutation in a human trace amine receptor gene. Genomics 82, 531–536 (2003)
Montmayeur, J. P., Liberles, S. D., Matsunami, H. & Buck, L. B. A candidate taste receptor gene near a sweet taste locus. Nature Neurosci. 4, 492–498 (2001)
Serizawa, S. et al. Negative feedback regulation ensures the one receptor–one olfactory neuron rule in mouse. Science 302, 2088–2094 (2003)
Durocher, Y. et al. A reporter gene assay for high-throughput screening of G-protein-coupled receptors stably or transiently expressed in HEK293 EBNA cells grown in suspension culture. Anal. Biochem. 284, 316–326 (2000)
Krautwurst, D., Yau, K. W. & Reed, R. R. Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95, 917–926 (1998)
Kajiya, K. et al. Molecular bases of odor discrimination: reconstitution of olfactory receptors that recognize overlapping sets of odorants. J. Neurosci. 21, 6018–6025 (2001)
Paulos, M. A. & Tessel, R. E. Excretion of β-phenethylamine is elevated in humans after profound stress. Science 215, 1127–1129 (1982)
Snoddy, A. M., Heckathorn, D. & Tessel, R. E. Cold-restraint stress and urinary endogenous β-phenylethylamine excretion in rats. Pharmacol. Biochem. Behav. 22, 497–500 (1985)
Grimsby, J. et al. Increased stress response and β-phenylethylamine in MAOB-deficient mice. Nature Genet. 17, 206–210 (1997)
Gavaghan McKee, C. L., Wilson, I. D. & Nicholson, J. K. Metabolic phenotyping of nude and normal (Alpk:ApfCD, C57BL10J) mice. J. Proteome Res. 5, 378–384 (2006)
Nishimura, K., Utsumi, K., Yuhara, M., Fujitani, Y. & Iritani, A. Identification of puberty-accelerating pheromones in male mouse urine. J. Exp. Zool. 251, 300–305 (1989)
Price, M. A. & Vandenbergh, J. G. Analysis of puberty-accelerating pheromones. J. Exp. Zool. 264, 42–45 (1992)
Lee, M. B., Storer, M. K., Blunt, J. W. & Lever, M. Validation of 1H NMR spectroscopy as an analytical tool for methylamine metabolites in urine. Clin. Chim. Acta 365, 264–269 (2006)
Novotny, M. V. Pheromones, binding proteins and receptor responses in rodents. Biochem. Soc. Trans. 31, 117–122 (2003)
Del Punta, K. et al. Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes. Nature 419, 70–74 (2002)
Wittwer, C. T., Herrmann, M. G., Moss, A. A. & Rasmussen, R. P. Continuous fluorescence monitoring of rapid cycle DNA amplification. Biotechniques 22, 130–139 (1997)
Clipstone, N. A. & Crabtree, G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992)
Acknowledgements
We thank S. Serizawa and Hitoshi Sakano for generously providing MOR28 transgenic mice. We also thank K. Wilson and R. Childs for technical assistance, and members of the Buck laboratory for helpful comments. This project was supported by the Howard Hughes Medical Institute and by grants from the National Institutes of Health (NIDCD).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Supplementary information
Supplementary Notes
Supplementary Figure 1 shows OE tissue stained with X-gal. Supplementary Data shows a brief summary of ligands identified for TAARs, along with EC50s where determined. Supplementary Methods shows a list of chemicals tested for their ability to activate TAARs. (PDF 1097 kb)
Rights and permissions
About this article
Cite this article
Liberles, S., Buck, L. A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006). https://doi.org/10.1038/nature05066
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature05066
This article is cited by
-
From odor to oncology: non-canonical odorant receptors in cancer
Oncogene (2024)
-
CD20/MS4A1 is a mammalian olfactory receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators
Nature Communications (2024)
-
Genomic features for adaptation and evolutionary dynamics of four major Asian domestic carps
Science China Life Sciences (2024)
-
Calcium imaging of adult olfactory epithelium reveals amines as important odor class in fish
Cell and Tissue Research (2024)
-
In situ hybridization analysis of olfactory receptor expression in the sea turtle olfactory organ
Cell and Tissue Research (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.