About

Hiroaki Matsunami is a Professor of Molecular Genetics and Microbiology, Minnie Geller Distinguished Professor in Genetics, Professor of Neurobiology, Professor of Cell Biology, and a member of several interdisciplinary institutes at Duke University, including the Duke Cancer Institute Faculty Network and the Duke Institute for Brain Sciences. He earned his bachelor's degree in Biology from Kyoto University in 1991, followed by a master's degree in 1993 and a Ph.D. in 1996, where he studied 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, where he identified a family of vomeronasal chemosensory receptors (V2Rs) and, together with Dr. Jean-Pierre Montmayeur, discovered a family of bitter taste receptors (T2Rs). His work was acknowledged by Dr. Buck in her Nobel lecture, as she and Dr. Richard Axel were awarded the 2004 Nobel Prize in Physiology or Medicine. Since establishing his own lab at Duke University in 2001, Dr. Matsunami has focused on elucidating the molecular mechanisms underlying mammalian chemosensation, including taste and smell. His lab identified the RTP family of accessory proteins that enable functional expression of mammalian odorant receptors (ORs) in heterologous cells, overcoming a major challenge in the field and enabling high-throughput deorphanization of ORs. His research demonstrated that genetic variation in human ORs, such as OR7D4, affects odor perception and food preference, marking the first characterization of the genetic basis of specific anosmia. His group has identified active ligands for over 50 mammalian ORs, characterized functional evolution of OR orthologs in primates and rodents, and revealed the role of non-OR G-protein coupled receptors and extracellular metal ions in modulating OR activation. Additionally, his lab discovered that most human odorant receptors have genetic polymorphisms that alter function, suggesting high inter-individual variability in odor detection. Dr. Matsunami's research addresses fundamental questions about how thousands of chemicals interact with a large repertoire of chemosensory receptors, how sensory information is coded in the brain, and how it directs behavior. His work spans the detection mechanisms of tastants, odorants, and pheromones, including the organization and regeneration of sensory cells and synaptic connections. His contributions have significantly advanced understanding of the molecular basis of chemical senses and their genetic and functional diversity in mammals.

Research topics

• Biology
• Neuroscience
• Immunology
• Genetics
• Virology
• Chemistry
• Medicine
• Cell biology
• Pathology
• Biochemistry

Selected publications

• Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors

  Zenodo (CERN European Organization for Nuclear Research) · 2026-04-01

  articleOpen access

  This file contains the MD simulation trajectories associated with the manuscript titled "Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors".

  PublisherDOI

• Decoding Smell from Receptor Structure

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-24

  articleOpen accessSenior authorCorresponding

  Abstract Olfaction enables animals to detect and discriminate a vast array of chemicals, yet how odorant receptors (ORs) encode ligand selectivity remains unclear. Although recent advances in protein structure prediction have expanded access to OR structures, linking these to function at scale has been challenging. Here, we combined AlphaFold3-predicted receptor structures with protein language model embeddings and in vivo pS6-IP-Seq measurements of olfactory sensory neuron activation across a chemically diverse odor panel to train a deep learning model of OR-ligand interactions. The resulting framework predicts receptor responses, organizes receptors by functional similarity independent of sequence, and identifies structural determinants of ligand selectivity. These findings establish a structure-based map of OR function and provide a foundation for predictive and interpretable models of olfactory coding.

  PublisherOA PDFDOI

• Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors

  Zenodo (CERN European Organization for Nuclear Research) · 2026-04-01

  articleOpen access

  This file contains the MD simulation trajectories associated with the manuscript titled "Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors".

  PublisherDOI

• Author response: Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

  2025-06-30

  peer-reviewOpen access

  Hormonal manipulation, laser microdissection, and bulk RNA sequencing indicate that Z chromosome dosage in the brain region HVC during development regulates the subsequent sexually dimorphic transcriptional specialization of zebra finch song nuclei.

  PublisherDOI

• Olfactory training in specific anosmia to androstenone and its association with genetic variations of OR7D4

  IBRO Neuroscience Reports · 2025-07-03 · 1 citations

  articleOpen access

  Short-term, repeated exposure to odors, "olfactory training" (OT), improves olfactory function. Clinically, this works not only for trauma- or disease-related olfactory impairment but also in people with specific anosmia. Androstenone is an odorant for which the frequent occurrence of specific anosmia is already known. It is an odorous steroid derived from testosterone. Besides some people who cannot perceive the odor, it is perceived differently by different individuals in terms of odor quality. These differences in the ability to perceive androstenone as well as in the perception of its quality were previously related to single nucleotide polymorphisms of the human olfactory receptor OR7D4. The current study addressed the question of whether changes in the perception of androstenone in relation to a change in sensitivity following specific OT with that odorant are associated with genetic variations of OR7D4. A total of 335 healthy volunteers participated (206 females, 129 males). All participants underwent tests for normal olfactory function; 103 showed specific anosmia for androstenone. Seventy-seven participants initially unable to perceive androstenone performed OT for an average duration of 8 weeks. Detection thresholds as well as subjective evaluation of odor intensity and pleasantness were measured both before and after OT. Buccal swabs were taken to examine the OR7D4 genotype. The study provided the following major results: (1) Detection thresholds were significantly lower after OT. (2) There was no statistically significant impact of the OR7D4 genotype on the ability to perceive androstenone after OT. In conclusion, it appears that the ability to perceive androstenone can be trained in people with specific anosmia, although OR7D4 polymorphisms were not related to a major change in the sensitivity towards androstenone.

  PublisherOA PDFDOI

• Tppp3 determines basal body positioning and identity of respiratory cilia via microtubule assembly and sphingolipid homeostasis

  Proceedings of the National Academy of Sciences · 2025-12-01

  articleOpen access

  Cilia are hair-like organelles that protrude from the cell surface. In mammals, tracheal multiciliated cells (MCCs) play an important role in elimination of hazardous microorganisms by driving a unidirectional mucus flow. Although uniform orientation of ciliary beating is critical for the unidirectional flow, it remains unknown how MCCs establish uniform orientations and maintain identities of hundreds of ciliary membranes. This study focuses on investigating the roles of Tubulin Polymerization Promoting Family Member 3 (Tppp3) in MCC function. We generated a Tppp3-deficient mouse ( Tppp3 ∆ex2-4/∆ex2-4 ; Tppp3 knockout (KO)) and found that the Tppp3 KO mouse exhibited cough and hyposmia phenotype. The loss of Tppp3 disrupted the apical microtubules (MTs) meshwork in the tracheal MCCs, leading to random orientation and alignment of basal bodies (BBs) of the motile cilia. Unexpectedly, aberrant ciliary membrane fusions occurred in the trachea of the Tppp3 KO mice. We examined the underlying molecular mechanism of the ciliary membrane fusion by isolating the tracheal cilium. Liquid Chromatography-Mass Spectrometry (LC–MS) analysis as well as pharmacological analysis revealed that hyperaccumulation of a long chain ceramide at the ciliary membrane caused the membrane fusion. In addition, sensory cilia formation was impaired in the olfactory sensory neuron of the Tppp3 KO mice. Due to the lack of Tppp3, dendritic MT assembly that underlies long-range migration of BBs toward the cell surface was impaired. These findings demonstrate that Tppp3, as well as the defined intracellular MT architecture, regulate proper orientation/subcellular positioning of BBs and the independency of individual motile cilium membranes.

  PublisherOA PDFDOI

• Identifying Key Regulators in Odorant Receptor Trafficking

  Journal of Neuroscience · 2025-10-22

  articleOpen accessSenior author

  Odor detection in mammals is primarily mediated by odorant receptors (ORs), the largest family of G-protein-coupled receptors, expressed in olfactory sensory neurons (OSNs; Buck and Axel, 1991). However, most ORs exhibit little or no cell surface expression in nonolfactory cell types (Lu et al., 2003; Hague et al., 2004). While the accessory protein RTP1 and RTP2 enhance the expression of certain ORs, we hypothesized that additional proteins coregulated with RTP1 and RTP2 during OSN maturation may further enhance OR cell surface expression (Saito et al., 2004; Zhuang and Matsunami, 2007). To test this, we developed a computational pipeline based on publicly available single-cell transcriptomic data to create an interactive tool for exploring gene expression during OSN maturation. Using this tool, we identified genes coregulated with Rtp1 during olfactory development. Three genes-Gfy, Clgn, and Syt1-exhibited transcriptional profiles similar to Rtp1. When coexpressed with an OR, these genes, in combination with Rtp1, promoted cell-surface expression of the tested ORs. Importantly, we demonstrated a physical interaction between Syt1 and an OR (Or1ad1) via co-immunoprecipitation, suggesting a novel role for Syt1 in OR trafficking or stabilization. We also observed localization of Syt1 protein in OSN cilia in both male and female mice. Together, these findings provide new insights into OSN development and the molecular mechanisms underlying OR biogenesis, paving the way for further research into the functional regulation of the olfactory systems.

  PublisherOA PDFDOI

• An odorant receptor for a key odor constituent of ambergris

  Communications Biology · 2025-05-23 · 2 citations

  articleOpen access

  Ambergris, a substance derived from the digestive system of sperm whales, has been valued for centuries for its unique aromatic properties. However, historical accounts indicate that certain human populations, particularly in East Asia, utilized ambergris without regard for its odor quality. These observations suggest that ambergris offers a model for studying how pleasant olfactory perception and its regional variations are constructed. Despite its historical and cultural significance, the molecular basis of ambergris perception has remained unclear. Here, we identified OR7A17 as an odorant receptor tuned to (-)-Ambroxide, a key odorant in ambergris. Analysis of genetic and functional variations in OR7A17 revealed that non-functional alleles of this receptor are prevalent in human populations, especially in East Asia. Individuals lacking functional OR7A17 alleles could still detect (-)-Ambroxide but found its scent less pleasant compared to those with functional alleles. These findings elucidate a molecular mechanism that influences the perceived pleasantness of ambergris and shed light on its enduring legacy in perfumery.

  PublisherOA PDFDOI

• Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

  eLife · 2025-02-24

  preprintOpen access

  Zebra finches are sexually dimorphic vocal learners. Males learn to sing by imitating mature conspecifics, but females do not. Absence of song in females is associated with partial atrophy and apparent repression of several vocal learning brain regions during development. However, atrophy can be prevented and vocal learning retained in females when given early pharmacological estrogen treatment. To screen for candidate drivers of this sexual dimorphism, we performed an unbiased transcriptomic analysis of song learning nuclei specializations relative to the surrounding regions from either sex, treated with vehicle or estrogen until 30 days old when divergence between the sexes becomes anatomically apparent. Analyses of transcriptomes by RNA sequencing identified song nuclei-specialized gene expressed modules associated with sex and estrogen manipulation. Female HVC and Area X gene modules were specialized by estrogen supplementation, exhibiting a subset of the transcriptomic specializations observed in males. Female RA and LMAN specialized modules were less dependent on estrogen. The estrogen-induced gene modules in females were enriched for anatomical development functions and strongly correlated to the expression of several Z sex chromosome genes. We present a hypothesis where reduced dosage and expression of these Z chromosome genes suppresses the full development of the song system and thus song learning behavior, which is partially rescued by estrogen treatment.

  PublisherDOI

• Physiology of olfactory sense

  Elsevier eBooks · 2025-01-01 · 1 citations

  book-chapterSenior author
  PublisherDOI

Recent grants

• NIH Grant R01DC010857

  NIH · $1.6M · 2015

• Biogenesis of olfactory G protein-coupled receptors

  NIH · $2.2M · 2017–2024

• Collaborative Research: Analysis of the Mammalian Olfactory Code

  NSF · $1.3M · 2015–2020

• US-French Research Proposal: Collaborative Research: Predicting Odorant-dependent and Independent Olfactory Neuron Activation Based on Receptor

  NSF · $271k · 2015–2019

• NIH Grant R01DC005782

  NIH · $3.5M · 2014

Frequent coauthors

• Claire A. de March

  Centre National de la Recherche Scientifique

  223 shared

• Hanyi Zhuang

  Ruijin Hospital

  111 shared

• Joel D. Mainland

  University of Pennsylvania

  104 shared

• Jérôme Golebiowski

  Daegu Gyeongbuk Institute of Science and Technology

  88 shared

• Yosuke Fukutani

  Tokyo University of Agriculture and Technology

  87 shared

• Yoshiro Ishimaru

  Meiji University

  75 shared

• Kentaro Ikegami

  Astellas Pharma (Japan)

  74 shared

• Qiuyi Chi

  Duke University

  67 shared

Labs

• Matsunami LabPI

Education

• Ph.D., Molecular and Cell Biology

  University of California, San Francisco

  1999

• B.S., Molecular and Cell Biology

  University of California, Berkeley

  1994