166 Ann. N.Y. Acad. Sci. 1047: 166–172 (2005). © 2005 New York Academy of Sciences. doi: 10.1196/annals.1341.015 Caveolae and Lipid Rafts G Protein–Coupled Receptor Signaling Microdomains in Cardiac Myocytes PAUL A. INSEL, a BRIAN P. HEAD, a RENNOLDS S. OSTROM, b HEMAL H. PATEL, a JAMES S. SWANEY, a CHIH-MIN TANG, c AND DAVID M. ROTH c a Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA b Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA c Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, USA ABSTRACT: A growing body of data indicates that multiple signal transduction events in the heart occur via plasma membrane receptors located in signaling microdomains. Lipid rafts, enriched in cholesterol and sphingolipids, form one such microdomain along with a subset of lipid rafts, caveolae, enriched in the protein caveolin. In the heart, a key caveolin is caveolin-3, whose scaffolding domain is thought to serve as an anchor for other proteins. In spite of the orig- inal morphologic definition of caveolae (“little caves”), most work related to their role in compartmenting signal transduction molecules has involved sub- cellular fractionation or immunoprecipitation with anti-caveolin antibodies. Use of such approaches has documented that several G protein–coupled recep- tors (GPCR), and their cognate heterotrimeric G proteins and effectors, local- ize to lipid rafts/caveolae in neonatal cardiac myocytes. Our recent findings support the view that adult cardiac myocytes appear to have different patterns of localization of such components compared to neonatal myocytes and cardiac fibroblasts. Such results imply the existence of multiple subcellular micro- domains for GPCR-mediated signal transduction in cardiac myocytes, in par- ticular adult myocytes, and raise a major unanswered question: what are the precise mechanism(s) that determine co-localization of GPCR and post-receptor components with lipid rafts/caveolae in cardiac myocytes and other cell types? KEYWORDS: adenylyl cyclase; cardiac fibroblast; cardiac myocyte; caveolin; G proteins; GPCR INTRODUCTION The transfer of information between the hydrophilic extracellular and intracellu- lar environments across the hydrophobic barrier of the plasma membrane is a funda- Address for correspondence: Prof. Paul A. Insel, M.D., Departments of Pharmacology and Medicine, University of California, San Diego, 9500 Gilman Drive, Mail code 0636, La Jolla, CA 92093, USA. Voice: 858-534-2295; fax: 858-822-1007. pinsel@ucsd.edu