[Jordan 1-17] Hosted by Thurl Harris.
My laboratory pursues the following two major lines of work.
GPCRs – Molecular Basis of Activation and Function
One major focus of my group is to understand how GPCRs function at the molecular level. GPCRs, one of the largest protein families found in nature, are cell-surface receptors that mediate the functions of an extraordinarily large number of extracellular ligands (neurotransmitters, hormones, etc.). The human genome contains approximately 800 distinct GPCR genes, corresponding to 3-4 percent of all human genes. Strikingly, 30-40 percent of drugs in current clinical use act on specific GPCRs. Understanding how GPCRs function at the molecular level is therefore of considerable therapeutic relevance. My lab uses different molecular, genetic, and biochemical strategies to address the following fundamental questions regarding the structure and function of these receptors: (1) How do GPCRs recognize and activate G proteins? (2) Which conformational changes do activating ligands induce in the receptor protein? (3) What is the structural basis and functional relevance of GPCR dimerization? My lab is also engaged in efforts, in collaboration with Dr. Brian Kobilka’s lab, to obtain high-resolution X-ray structures for members of the muscarinic receptor family of GPCRs. These studies should eventually lead to novel therapeutic approaches aimed at modulating the function of specific GPCRs.
Generation and Analysis of GPCR Mutant Mice to Explore GPCR Signaling and Physiology
Many of the important physiological functions of the neurotransmitter acetylcholine are caused by the interaction of acetylcholine with a group of GPCRs referred to as muscarinic receptors. Molecular cloning studies have revealed the existence of five molecularly distinct muscarinic receptor subtypes referred to as M1-M5. The M1-M5 receptors are abundantly expressed in most cells and tissues and are critically involved in regulating many fundamental physiological processes including, for example, the regulation of body weight and food intake, the release of insulin from pancreatic beta cells, and many key functions of the CNS including most cognitive processes. To elucidate the physiological roles of the individual muscarinic receptor subtypes, we are using gene-targeting techniques, including Cre/loxP technology, to generate mouse lines lacking functional M1-M5 muscarinic receptors, either throughout the body or only in certain tissues or cell types. Current phenotyping studies are focusing on the potential roles of the different muscarinic receptor subtypes in regulating energy and glucose homeostasis in various peripheral and central tissues.