Faculty

PAUL A. INSEL

Professor of Pharmacology and Medicine

Key Words: Catecholamines; Nucleotides; G Proteins; Adenylyl Cyclases; Signal Transduction

My laboratory is primarily involved in studying the signal transduction by certain G protein-coupled receptors (GPCR), in particular catecholamine and P2Y (nucleotide) receptors. Our approach focuses on the use of model systems with biochemical, cell biological and molecular biological techniques to ask questions about drug and hormone action. We utilize receptor binding methods, G protein assays, and studies of second messenger systems (e.g., cyclic AMP, phosphoinositide hydrolysis and arachidonic acid formation), and of more distal events, such as apopotosis. Current work focuses on compartmentation of signaling molecules, in particular in caveolin-rich membrane microdomains, and the role of adenylyl cyclase isoforms as limiting components in cyclic AMP generation. A second major thrust of the lab involves identification of genetic polymorphism in human GPCRs, adenylyl cyclases, and other G-protein pathway components, and assessment of the impact of such variants on cell and tissue function and response to drugs. We are applying these techniques to clinical conditions that have altered response to GPCR and for which the pathophysiologic cause may be altered GPCR, G proteins, Regulators of G-protein signaling (RGS) proteins or effector molecules

Torres B, Zambon AC and Insel PA. P2Y11 receptors activate adenylyl cyclase and contribute to nucleotide-promoted cAMP formation in MDCK-D(1) cells. A mechanism for nucleotide-mediated autocrine-paracrine regulation. J Biol Chem 277, 7761-5 [2002]

Buescher R, Eilmes KJ, Grasemann H, Torres B, Knauer N, Insel PA, Ratjen F. b₂-adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics 12,347-53 [2002]

Nishihara H, Kizaka-Kondoh S, Insel PA, Eckmann, L Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2. Proc Nat Acad Sci, USA 100, 8921-6 [2003].

Ostrom RS, Liu X, Head BP, Gregorian C, Seasholtz TM, Insel PA. Localization of adenylyl cyclase isoforms and G protein-coupled receptors in vascular smooth muscle cells: expression in caveolin-rich and noncaveolin domains. Mol Pharmacol 63, 983-92 [2002].

Bundey R and Insel PA. Quantification of adenylyl cyclase messenger RNA by real-time polymerase chain reaction. Anal .Biochem., 319,318-22 [2003]

Kirstein SL and Insel PA Autonomic nervous system pharmacogenomics: a progress report. Pharmacol. Rev. in press [2004].

Visit Dr. Insel's Home Page