Research Interests: 
Mechanisms of heterotrimeric G protein signaling, defining the roles of G proteins and their regulators in the cardiovascular system.

Detailed Description: 

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 Galpha subunit and a G beta gamma heterodimer. In the absence of an extracellular stimulus, the G-protein is coupled to a plasma membrane-spanning receptor (G protein-coupled receptor; GPCR). Receptor activation results in the exchange of GTP for GDP on the Galpha subunit and the dissociation of GTP-bound Galpha from the G beta gamma heterodimer. This condition marks the activated ("ON") state during which time the Galpha and G beta gamma subunits are free to engage appropriate downstream effector pathways. Effector signaling is terminated following Galphacatalysed hydrolysis of GTP and reformation of the quiescent receptor-coupled heterotrimer.

RGS proteins are a family of GTPase activating proteins (GAPs) for Galpha subunits. By increasing the intrinsic rate of GTP hydrolysis for Galpha 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.

VSMC Function in Disease Models:

Hypertension is a leading risk factor for cardiovascular disease in humans. My laboratory is interested in using genetic mouse models to understand the molecular pathways that regulate blood pressure at the level of the peripheral vasculature. Recently we discovered that mice lacking RGS2, a potent inhibitor of Gq signaling, are profoundly hypertensive and show prolonged vasoconstrictor signaling in the peripheral vasculature. We are currently determining the role of the vasculature, kidney and central nervous system in mediating this phenotype. We are using calcium imaging to study vasoconstrictor responses primary cultured VSMCs in vitro, vessel bath technologies to study vascular contractile function in situ and blood pressure measurements in surgically implanted mice to study whole animal physiology. Future studies are aimed at defining new therapeutic targets for the treatment of hypertension and heart disease.