The ligand selectivity of the three families of receptors expressed in the vomeronasal organ-V1Rs, V2Rs and FPRs-is largely unknown. To deepen our understanding of the interactions between the vomeronasal receptors and their ligands, we propose to establish systems to identify active ligands for the V2Rs and the FPRs. In addition, we propose to identify which domains of the receptor proteins determine ligand selectivity. To test the hypothesis that specific V2R or FPR vomeronasal receptors are activated by specific set of ligands, three Specific Aims are proposed:
Specific Aim 1. Characterize the ligand selectivity of V2Rs. We will establish a heterologous expression system for the V2Rs. We will use this system to identify active ligands of the V2Rs and examine the structural basis of ligand selectivity by V2R family members.
Specific Aim 2 : Characterize the ligand selectivity of VNO-FPRs. We will establish a heterologous expression system for the VNO-FPRs. We will use this system to identify the active ligands of VNO-FPRs.
Specific Aim 3 : Characterize the ligand selectivity of VNO receptors using VNO sensory neurons. We will establish a system for measuring the response of dissociated vomeronasal neurons using calcium imaging and then measuring the mRNA expression in the same cells. We will use this method to identify the receptors expressed in the cells activated by a given ligand. The proposed experiments further our long term goal, which is to understand the mechanistic basis for ligand recognition by the vomeronasal receptors. The health relatedness of these studies is that a better understanding of the ligand binding attributes of vomeronasal receptors will offer insights into the general features of ligand recognition by G-protein coupled receptors, a class of receptor that is frequently targeted by drugs. This work will improve our understanding of how G protein-coupled vomeronasal receptors recognize and discriminate specific ligands. This basic knowledge will translate to greater understanding of G protein-coupled receptors, which are major pharmaceutical targets for cardiac, psychiatric, and cancer disease states. An understanding of the interactions between the ligand and receptor provides crucial information needed to develop a wide range of health-related products.

Public Health Relevance

Vomeronasal receptors are thought to play an important role in detecting pheromones, although it is unclear which receptors are activated by which pheromones. Our goal is to deepen our understanding of the interactions between the vomeronasal receptors and their ligands. This work is relevant to improving public health, because a better understanding of the ligand binding attributes of vomeronasal receptors will offer insights into the protein-ligand interactions of G-protein coupled receptors, a class of receptors frequently targeted by pharmaceutical drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC010857-04
Application #
8440781
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sullivan, Susan L
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$300,645
Indirect Cost
$105,230
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Jiang, Yue; Gong, Naihua N; Matsunami, Hiroaki (2014) Astringency: a more stringent definition. Chem Senses 39:467-9
Li, Yun Rose; Matsunami, Hiroaki (2013) Unfolding the mystery of olfactory receptor gene expression. Dev Cell 27:128-9
Keydar, Ifat; Ben-Asher, Edna; Feldmesser, Ester et al. (2013) General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations. Hum Mutat 34:32-41
Dey, Sandeepa; Zhan, Senmiao; Matsunami, Hiroaki (2011) Assaying surface expression of chemosensory receptors in heterologous cells. J Vis Exp :
Dey, Sandeepa; Matsunami, Hiroaki (2011) Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors. Proc Natl Acad Sci U S A 108:16651-6
Chamero, Pablo; Katsoulidou, Vicky; Hendrix, Philipp et al. (2011) G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice. Proc Natl Acad Sci U S A 108:12898-903