Faculty Research Description
Research in my lab is directed at understanding the structural basis for the functional properties of G protein coupled receptors (GPCRs). GPCRs are nature's most versatile biological sensors. They conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. Adrenergic receptors, which transmit signals from sympathetic nerves to the cardiovascular system, are one of the most extensively characterized subfamilies of GPCRs, and serve as a model system for understanding the structure, cell biology, and physiology of GPCRs. We are investigating adrenergic receptors using a broad spectrum of approaches. These range from using protein crystallography and biochemical and biophysical tools to determine GPCR structure and elucidate ligand-induced conformational changes, to using in vitro and in vivo systems to determine the structural basis for more complex functional properties that are only observed in differentiated cells.
My group has developed direct methods to monitor ligand-induced conformational changes in purified beta 2 adrenergic receptor, and we we recently obtained a high-resolution crystal structure of this receptor. Our results suggest that agonists bind in a stepwise process in which some receptor-ligand interactions form rapidly, while other interactions cannot form until stochastic conformational fluctuations make the complete binding pocket accessible. Our data argue for a multi-state model of receptor activation, with different agonists inducing distinct active states.
We have also developed strains of knockout mice for five adrenergic receptor subtypes. These mice have provided insight into the physiologic role of specific receptor subtypes in vivo. Mice lacking both alpha 2A and alpha 2B adrenergic receptors have elevated sympathetic tone and develop heart failure by 4 months of age. We are using these mice as a model system to gain insight into the pathogenesis and treatment of heart failure in humans. From studies of beta adrenergic receptor knockout mice we found that beta 1 and beta 2 adrenergic receptors play unique roles in regulating cardiovascular function. We are using neonatal myocytes from beta1/beta2 adrenergic receptor double knockout mice as a differentiated expression system to study the structural basis for differences in the functional properties of these two receptors. Our studies suggest that functional differences between beta 1 and beta 2 addrenergic receptors are due to their localization in different plasma membrane signaling compartments.