My laboratory focuses on the analysis of G protein-coupled receptors (GPCRs)—one of the largest protein families found in nature. GPCRs are receptors on the surfaces of cells. A large number of important chemicals in the body—including neurotransmitters, which carry signals from cell to cell, and hormones, which carry signals from one part of the body to another—bind to GPCRs. GPCRs mediate the functions of these critical chemical messengers. Two striking facts illustrate the essential contributions of GPCRs: (1) the entirety of our hereditary information (the human genome) contains approximately 800 distinct GPCR genes, corresponding to 3 to 4 percent of all human genes; (2) 30 to 40 percent of medications act on specific GPCRs.
One major focus of our research is to understand how GPCRs function at the molecular level, because this can ultimately promote the development of better treatments. As indicated by the name, GPCRs are linked to G proteins, which act as a molecular switch that is biochemically turned “on” or “off” within the cell. We use different molecular, genetic, and biochemical strategies to address the following fundamental questions regarding the structure and function of these receptors: (1) How do GPCRs interact with G proteins and other GPCR-associated proteins? (2) When an activating agent binds to the receptor, how does the shape of the receptor protein change? (3) What is the precise structure of these receptors? For many of these studies, we use a subgroup of GPCRs referred to as muscarinic acetylcholine receptors as a model system.
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 biologists have identified five distinct muscarinic receptors that differ in their amino acid sequences (M1-M5). These receptors regulate many important physiological activities—including, for example, body weight and food intake, the release of insulin from pancreatic beta cells, and most processes that underlie memory and learning. In many cases, it is still unclear which specific muscarinic receptor subtypes are involved in these various physiological functions. To address this issue, we are generating mutant mice that lack individual muscarinic receptors, either throughout the body or only in certain tissues or cell types. Importantly, we are studying the physical traits of these mice, particularly how blood glucose levels and body weight are affected by the lack of specific receptors.
In a related line of work, we are using a new strategy that allows us to activate specific classes of G proteins in specific cell types, including pancreatic beta-cells, and cells in the liver, muscle, and hypothalamus, a brain structure that regulates many physiological functions including food intake and body weight. Specifically, we are expressing modified GPCRs with distinct ligand binding and signaling properties in a cell type specific fashion in transgenic mice. The aim of these studies is to identify new biological targets for the development of treatments for various conditions, including type 2 diabetes and obesity.