Professor of Neurobiology
Member of the Duke Cancer Institute
Faculty Network Member of the Duke Institute for Brain Sciences
Professor of Cell BIology
Associate of the Duke Initiative for Science & Society
Box 3054 DUMC
Durham, N.C. 27710
Phone: (919) 684-2777
Fax: (919) 681-9193
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.
Hiroaki Matsunami earned his bachelor’s degree in Biology from Kyoto University in 1991. He went on to earn his master’s degree in 1993 and his Ph.D. in 1996 in Dr. Masatoshi Takeichi’s lab studying the role of cadherin cell adhesion molecules during brain development in mammals.
Dr. Matsunami completed his postdoctoral training in Dr. Linda Buck’s lab at Harvard University. There, he conducted a number of projects involving the identification of new mammalian chemosensory receptors. First, Dr. Matsunami identified a family of chemosensory receptors, V2Rs, which are expressed in the vomeronasal organ, a second olfactory organ implicated in detection of pheromones and other semiochemicals. Second, together with Dr. Jean-Pierre Montmayeur, he identified a family of bitter taste receptors, T2Rs. Drs. Linda Buck and Richard Axel were awarded the 2004 Nobel Prize in Physiology or Medicine. In her Nobel lecture, Dr. Buck mentioned his work and acknowledged his contributions.
In 2001, Dr. Matsunami moved to Duke University to start his own lab with the goal of deepening our understanding of molecular mechanisms underlying olfaction and other chemical senses.
As an assistant professor, Dr. Matsunami’s lab identified the RTP family of accessory proteins that induce functional expression of mammalian ORs in heterologous cells. This finding overcame a long-standing challenge in the field and promoted the establishment of a platform for high-throughput “deorphanization” of mammalian ORs. In collaboration, Dr. Matsunami demonstrated that functional variation of a human OR, OR7D4, affects odor perception of its cognate ligand androstenone. This was the first characterization of the genetic basis of a specific anosmia. In addition, Dr. Matsunami contributed to the identification of candidate sour taste receptors as well as an elucidation of CO2 detection in rodents.
As an associate professor, Dr. Matsunami’s group identified active ligands for over 50 mammalian ORs using a heterologous expression system that his lab developed. This was the first large-scale characterization of odorants-odorant receptor pairs in mammals. His group investigated functional evolution of OR orthologs in primates and rodents and demonstrated dynamic changes in responses between related species. His lab showed that OR7D4 affects the human preference for pork containing androstenone, the first demonstration that ORs contribute to food preference. To deepen our understanding of olfactory transduction, Dr. Matsunami’s lab showed the activation state of the M3 muscarinic acetylcholine receptor, a non-OR GPCR, modulates OR signaling. In collaboration, his group showed a crucial role of extracellular copper ion in OR activation by thiol odors, the first demonstration of metal ion involvement in OR function. His lab showed the role of calreticulin chaperones in preventing functional expression of V2R pheromone receptors outside the vomeronasal organ, where expression of calreticulin is sparse. This finding paved the way towards functional characterization of V2R members. Lastly, Dr. Matsunami’s lab found that the majority of human odorant receptors have genetic polymorphisms that alter function. On average, two individuals have functional differences at over 30% of their odorant receptor alleles. This unusually high level of functional variability in the primary receptors transducing olfactory information is strongly suggestive of high inter-individual variability in odor detection at the receptor level.
In summary, as an independent investigator, Dr. Matsunami made contributions in the field of chemical senses, first by establishing a method to functionally express mammalian ORs through the discovery of key accessory proteins. Using this as a platform, Dr. Matsunami’s lab identified a large number of active ligands for many ORs, characterized OR variants and determined contributions of ORs in odor perception and food preference, and found important roles that a non-OR GPCR as well as extracellular metal ions play in OR activation.
As a graduate student, Dr. Matsunami received a JSPS pre-doctoral fellowship. During his post-doctoral training period, he received a Naito Foundation and JSPS postdoctoral fellowships. As an assistant professor, Dr. Matsunami received a Human Frontier Science Program (HFSP) Young Investigator grant with Dr. Luo. Dr. Matsunami is an American Association for the Advancement of Science (AAAS) fellow. He serves as an academic editor for the journals PLoS One and PeerJ.
Harumi Saito, Senior Research Associate, University of Tokyo
Yoshiro Ishimaru, Associate Professor, Meiji University
Joel Mainland, Associate Professor, Monell Chemical Senses Center
Hanyi Zhuang, Professor, Shanghai Jiaotong University
Richard Roberts, Postdoctoral Fellow, Washington University
Sandeepa Dey, Postdoctoral Fellow, Scripps Institute
Kaylin Adipietro, Research Associate, University of Maryland
Jianghai Ho, Master Student in Music
Yue Jiang, Research Scientist, Juno Therapeutics
Mingshan Chien, Research Scientist, International Flavors & Frangrances
Ruchira Neha Sharma, Postdoctoral Fellow, UCSF
Aubrey Bonhivert, MD Student, Ohio St University
Yun Rose Li, MD/PhD Student, University Penn
Senmiao Mimi Zhan, MD Student, UNC
Peter Yi Dong, PhD Student, University Penn
Nauhua Natalie Gong, Md/PhD Student, University Penn
Zoya Qureshy, MD Student, UCSF
Akhil Sharma, MD Student, University Miami
Safa Kaleem, MD Student, Duke
ELise Bruguera, PhD Student, Standford
Helena You, MD Student UT Southwestern
Vihani, A., Hu, X.S., Gundala, S., Koyama, S., Block, E., and Matsunami, H. (2020). Semiochemical responsive olfactory sensory neurons are sexually dimorphic and plastic. eLife 9.
Kaba, H., Fujita, H., Agatsuma, T., and Matsunami, H. (2020). Maternally inherited peptides as strain-specific chemosignals. Proceedings of the National Academy of Sciences of the United States of America 117, 30738-30743.
Ikegami, K., de March, C.A., Nagai, M.H., Ghosh, S., Do, M., Sharma, R., Bruguera, E.S., Lu, Y.E., Fukutani, Y., Vaidehi, N., Yohda, M., and Matsunami, H. (2020). Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors. Proceedings of the National Academy of Sciences of the United States of America 117, 2957-2967.
Hu, X.S., Ikegami, K., Vihani, A., Zhu, K.W., Zapata, M., de March, C.A., Do, M., Vaidya, N., Kucera, G., Bock, C., Jiang, Y., Yohda, M., and Matsunami, H. (2020). Concentration-Dependent Recruitment of Mammalian Odorant Receptors. eNeuro 7.
Durante, M.A., Kurtenbach, S., Sargi, Z.B., Harbour, J.W., Choi, R., Kurtenbach, S., Goss, G.M., Matsunami, H., and Goldstein, B.J. (2020). Single-cell analysis of olfactory neurogenesis and differentiation in adult humans. Nature neuroscience 23, 323-326.
de March, C.A., Titlow, W.B., Sengoku, T., Breheny, P., Matsunami, H., and McClintock, T.S. (2020). Modulation of the combinatorial code of odorant receptor response patterns in odorant mixtures. Molecular and cellular neurosciences 104, 103469.
Brann, D.H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., Chance, R., Macaulay, I.C., Chou, H.J., Fletcher, R.B., Das, D., Street, K., de Bezieux, H.R., Choi, Y.G., Risso, D., Dudoit, S., Purdom, E., Mill, J., Hachem, R.A., Matsunami, H., Logan, D.W., Goldstein, B.J., Grubb, M.S., Ngai, J., and Datta, S.R. (2020). Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv 6.
Trimmer, C., Keller, A., Murphy, N.R., Snyder, L.L., Willer, J.R., Nagai, M.H., Katsanis, N., Vosshall, L.B., Matsunami, H., and Mainland, J.D. (2019). Genetic variation across the human olfactory receptor repertoire alters odor perception. Proceedings of the National Academy of Sciences of the United States of America 116, 9475-9480.
Torres-Torrelo, H., Ortega-Saenz, P., Macias, D., Omura, M., Zhou, T., Matsunami, H., Johnson, R.S., Mombaerts, P., and Lopez-Barneo, J. (2018). The role of Olfr78 in the breathing circuit of mice. Nature 561, E33-E40.
Kida, H., Fukutani, Y., Mainland, J.D., de March, C.A., Vihani, A., Li, Y.R., Chi, Q., Toyama, A., Liu, L., Kameda, M., Yohda, M., and Matsunami, H.(2018). Vapor detection and discrimination with a panel of odorant receptors. Nat Commun 9, 4556.
E, L., Zhou, T., Koh, S., Chuang, M., Sharma, R., Pujol, N., Chisholm, A.D., Eroglu, C., Matsunami, H., and Yan, D. (2018). An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection. Neuron 97, 125-138 e125.
de March, C.A., Topin, J., Bruguera, E., Novikov, G., Ikegami, K., Matsunami, H., and Golebiowski, J. (2018). Odorant Receptor 7D4 Activation Dynamics. Angew Chem Int Ed Engl 57, 4554-4558.
Abaffy, T., Bain, J.R., Muehlbauer, M.J., Spasojevic, I., Lodha, S., Bruguera, E., O’Neal, S.K., Kim, S.Y., and Matsunami, H. (2018). A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor. Front Oncol 8, 162.
Sharma, R., Ishimaru, Y., Davison, I., Ikegami, K., Chien, M.S., You, H., Chi, Q., Kubota, M., Yohda, M., Ehlers, M., and Matsunami, H. (2017). Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice. eLife 6.
Zhou, T., Chien, M.S., Kaleem, S., and Matsunami, H. (2016). Single cell transcriptome analysis of mouse carotid body glomus cells. The Journal of physiology.
Jiang, Y., Gong, N.N., Hu, X.S., Ni, M.J., Pasi, R., and Matsunami, H. (2015). Molecular profiling of activated olfactory neurons identifies odorant receptors for odors in vivo. Nature neuroscience 18, 1446-1454.
de March, C.A., Yu, Y., Ni, M.J., Adipietro, K.A., Matsunami, H., Ma, M., and Golebiowski, J. (2015). Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors. Journal of the American Chemical Society.
Dey, S., Chamero, P., Pru, J.K., Chien, M.S., Ibarra-Soria, X., Spencer, K.R., Logan, D.W., Matsunami, H., Peluso, J.J., and Stowers, L. (2015). Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior. Cell 161, 1334-1344.
Jiang, Y., Li, Y.R., Tian, H., Ma, M., and Matsunami, H. (2015). Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of beta-arrestin-2 recruitment. Nat Commun 6, 6448.
Ho, J., Perez-Aguilar, J.M., Gao, L., Saven, J.G., Matsunami, H., and Eckenhoff, R.G. (2015). Molecular recognition of ketamine by a subset of olfactory G protein-coupled receptors. Sci Signal 8, ra33.
Mainland, J.D., Keller, A., Li, Y.R, Zhou, T. Snyder, L.L., Moberly, A.H., Adipietro, K.A., Liu, W.L.L., Zhuang, H., Zhan, S., Lee, S.S., Lin, A., and H. Matusunami. (2014). The missense of smell: Functional variability in the human odorant receptor repertoire. Nat Neurosci, Jan;17(1):114-120. [Epub 2013 Dec 8].
Adipietro, K.A., J.D. Mainland, and H. Matsunami. (2012). Functional evolution of mammalian odorant receptors. PLoS Genet, 8(7):e1002821.
Dey, S. and H. Matsunami. (2011). Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors. Proc Natl Acad Sci U S A, 108(40):16651-16656.
Li, Y.R. and H. Matsunami (2011). Activation state of the M3 muscarinic acetylcholine receptor modulates mammalian odorant receptor signaling. Sci Signal, 4(155): ra1.
Zhuang, H., Chien, M.S., Matsunami, H. (2009). Dynamic functional evolution of an odorant receptor for sex-steroid-derived odors in primates. Proc Natl Acad Sci U S A, 106:21247-21251.
Saito, H., Chi, Q., Zhuang, H., Matsunami, H., Mainland, J.D. Odor coding by a mammalian receptor repertoire. (2009). Sci Signal, 2:ra9.
Zhuang, H., and Matsunami, H. (2008). Evaluating cell-surface expression and measuring activation of mammalian ordorant receptors in heterologous cells. Nat Protoc, 3: 1402-1413.
Keller, A., Zhuang, H., Chi, Q., Vosshall, L.B., Matsunami, H. (2007). Genetic variation in a human odorant receptor alters odour perception. Nature, 449: 468-472.
Hu, J., Zhong, C., Ding, C., Chi, Q., Walz, A., Mombaerts, P., Matsunami, H., Luo, M. (2007). Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse. Science, 317:953-957.
Zhuang, H., and Matsunami, H. (2007). Synergism of accessory factors in functional expression of mammalian odorant receptors. J Biol Chem, 282:15284-15293.
Ishimaru, Y., Inada, H., Kubota, M., Zhuang, H., Tominaga, M., Matsunami, H. (2006). Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A, 103:12569-12574.
Saito, H., Kubota, M., Roberts, R.W., Chi, Q., and Matsunami, H. (2004). RTP family members induce functional expression of mammalian odorant receptors. Cell, 119:679-691.
Matsunami H., Montmayeur, J.P. and Buck, L.B. (2000). A family of candidate taste receptors in human and mouse. Nature, 404:601-604.
Matsunami, H. and Buck, L.B. (1997). A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell, 90:775-784.
For a complete listing of publications, click here.