Many physiologic processes are mediated by a group of switch-like heterotrimeric G proteins. G proteins are normally coupled to receptors on the cell surface to act as intracellular relays between environmental stimuli and the rest of the cell. Our work defines the biologic importance for precise kinetic regulation of G-protein-mediated signaling events.

Regulation of G-protein signaling pathways: The G-protein heterotrimer is composed of a GDP-bound G alpha subunit and a G beta gamma heterodimer. Upon G-protein activiation, the Galpha subunits are free to engage appropriate downstream effector pathways. Effector signaling is terminated following G alpha catalysed hydrolysis of GTP and reformation of the quiescent receptor-coupled heterotrimer. RGS proteins are a family of GTPase activating proteins (GAPs) for G alpha subunits. By increasing the intrinsic rate of GTP hydrolysis for G alpha subunits, RGS proteins impact GPCR-mediated signaling pathways by: i) promoting faster signal termination kinetics following removal of a physiologic GPCR agonist; and ii) decreasing GPCR agonist sensitivity (i.e. higher agonist concentrations are needed to achieve the same degree of signaling). Our work is aimed at defining the molecular mechanisms that regulate the function of RGS proteins in vivo . Using a combination of physiology, biochemistry, cell biology, pharmacology, and genetics we examine how subcellular localization, G-protein selectivity and interaction with other cellular signaling components regulates the function of RGS proteins in living organisms.

Regulation of G-protein signalling in Pancreatic Islet beta cells: Previous work has shown that one RGS protein family member, RGS4, is highly expressed in beta cells and its function can have profound physiologic effects on insulin secretion. Although the majority of the work in this field has been focussed on the role of RGS4 at the plasma membrane, our recent studies have identified a novel intracellular location for RGS4, the preautophagosome, where it can regulate the autophagic flux and metabolic homeostasis within beta cells. Notably, activated Galphai3 is a potent attenuator of autophagic activity. Accordingly, our work is aimed at understanding the role of RGS4 in the regulation of autophagic flux and enery homeostasis in pancreatic islet beta cells.