We are seeking to understand how cells “pre-arrange” multiple signaling components in GPCR signal transduction cascades and are focused on caveolae and lipid rafts as centers for such organization. Our long-term focus is to understand how such compartmentation impacts cellular response in a physiological setting.
Using molecular cloning, expression of cloned signaling proteins, and a variety of cell biological and biochemical approaches, we examine signaling mechanisms of G protein-coupled receptors. We are interested in the organization of signaling microdomains in the plasma membrane, especially in lipid raft/caveolin-rich regions, in which various receptors, G-proteins and effectors, particularly certain isoforms of adenylyl cyclase, localize. We seek to understand how such compartmentation impacts on cellular responses with the goal of developing novel gene therapy strategies to modulate cellular responses through changes in expression of limiting components in the signaling pathways. Adenylyl cyclase is one such limiting component. Currently, we study cardiac myocytes, cardiac fibroblasts, airway and GI smooth muscle cells and pulmonary fibroblasts.
We have found that certain isoforms of adenylyl cyclase localize in lipid rafts and caveolae while other isoforms are excluded from these plasma membrane microdomains. Because only certain G protein-coupled receptors are co-localized in lipid rafts/caveolae, receptors can selectively couple to a single adenylyl cyclase isoform despite expression of several different isoforms in a single cell. Such “compartmentation” may mean that receptors coupled to redundant signaling mechanisms can induce different cellular responses. We are also actively studying the structural basis of adenylyl cyclase localization in lipid rafts and caveolae.