GPCR anterograde trafficking

Summary G protein-coupled receptors (GPCRs) regulate a wide range of physiological and pathological processes and are important targets of therapeutics. As the cell surface is the functional destination for most GPCRs, defective cell surface delivery leads to GPCR dysfunction and is clearly associated with the pathogenesis of human diseases. However, the molecular mechanisms underlying the anterograde transport of nascent GPCRs from the endoplasmic reticulum (ER) to the cell surface en route pass through the Golgi apparatus remain poorly elucidated. In this proposal, we will define the roles of several newly identified regulators, including cargo receptors, ufmylation, protein complexes, post-Golgi carriers and exocyst, in the recruitment to COPII vesicles, ER-Golgi-cell surface delivery, and formation and plasma membrane tethering of Golgi- derived carriers of GPCRs. The proposed research is a continuation of our long-standing efforts to study the anterograde trafficking of GPCRs, which have led to the discovery of a number of structural determinants and regulatory proteins essential for GPCR export and segregation. As in the past, we will employ state-of- the-art biochemical, immunochemical and live cell imaging techniques to dissect the mechanistic aspects of GPCR trafficking along the biosynthetic pathway. These studies will reveal novel mechanisms that govern the forward trafficking and sorting of GPCRs and have a broad impact on the research of GPCR superfamily and general membrane trafficking. The information generated from these studies may create new avenues for drug design and treatment of diseases involving aberrant trafficking and function of GPCRs.