Biogenesis of olfactory G protein-coupled receptors

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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.