Biogenesis of G protein-coupled receptors (GPCRs), the largest molecular class of pharmaceutical targets for cardiac, psychiatric, and cancer diseases is a complex and underexplored process. Many GPCRs require the presence of specific accessory proteins or co-receptors for their cell surface trafficking and/or functional expression. We previously identified RTP1 (Receptor Transporting Protein 1) and RTP2, both of which are single transmembrane proteins strongly and exclusively expressed in the peripheral olfactory organs. They greatly enhance trafficking of olfactory receptors (ORs) on the cell surface and induce functional expression in heterologous cells. In preliminary studies we investigated the roles played by the RTPs in vivo using the RTP1 and RTP2 double gene knockout mice (RTP1,2(-/-)), and uncovered an unexpected link between OR trafficking and OR gene choice mediated by the RTPs. Based on these and other preliminary studies, we will test three hypotheses. These are 1) RTP1 and RTP2 influence OR gene choice, 2) RTP mutant animals use diminished repertoire of functional ORs, and 3) specific residues of ORs regulate ER retention and cell surface trafficking. The successful completion of the project will deepen our understanding of OR biogenesis and function, and sheds light on the new link between OR protein trafficking and OR transcriptional regulation.

Public Health Relevance

This project will deepen our understanding of how G protein-coupled odorant receptors are generated and trafficked to the cell membrane to respond to odorous molecules. This fundamental knowledge will advance the present understanding of G protein-coupled receptors, which are the largest molecular class of pharmaceutical targets for cardiac, psychiatric, and cancer diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC016224-02
Application #
9484271
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Abaffy, Tatjana; Bain, James R; Muehlbauer, Michael J et al. (2018) A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor. Front Oncol 8:162
Kida, Hitoshi; Fukutani, Yosuke; Mainland, Joel D et al. (2018) Vapor detection and discrimination with a panel of odorant receptors. Nat Commun 9:4556