UR Faculty: Alan V. Smrcka, Ph.D.

G protein coupled receptors (GPCRs) form a large family of cell surface receptors responsible for triggering cellular responses to a variety of extracellular stimuli including drugs such as opiates, and hormones such as adrenaline, serotonin or acetylcholine. All GPCRs function through activation of trimeric G proteins located on the inner surface of the plasma membrane. Activated G proteins target ion channels or enzymes that produce second messengers with a variety of effects depending on the type of cell that is stimulated. Examples include regulation of synaptic transmission in the central nervous system, chemotaxis in the immune system, and vascular remodeling in the cardiovascular system. This family of receptors is an important target for pharmaceuticals and defects in GPCR systems are responsible for a number of diseases.

Our laboratory focuses on analysis of the interactions between the G proteins and their protein targets at a molecular and structural level with the goal of understanding how these interactions lead to alterations in protein and cellular activities. Another goal is to connect the biochemical information about protein interaction interfaces to specific cellular physiologies. To this end we are developing antagonists of specific G protein interactions and using these tools to probe the functions of those interactions in living cells. This approach will help to define the roles of specific G protein interactions in physiological processes and as potential targets for therapeutic intervention in cardiovascular disease or cancer.

Recent Publications

Ghosh, M. and Smrcka, A.V. (2004) Assay for G protein-dependent activation of phospholipase C beta using purified protein components. Methods Mol. Biol. 237:67-75.

Ghosh, M., Wang, H., Kelley, G.G., and Smrcka, A.V. (2004) Purification of phospholipase C beta and phospholipase C epsilon from Sf9 cells. Methods Mol. Biol. 237:55-64.

Kelley, G.G., Reks, S.E., Smrcka, A.V. (2004) Hormonal regulation of phospholipase C beta through distinct and overlapping pathways involving G12 and Ras family G proteins. Biochem J. 378:129-139.

Shajahan, A.N., Tiruppathi, C., Smrcka, A.V., Malik, A.B., and Minshall, R.D. (2004) Gbg activation of Src induces caveolae-mediated endocytosis in endothelial cells. J Biol Chem 279:48055-48062.

Smrcka, A.V., Ed. (2004) G Protein Signaling: Methods and Protocols, Humana Press, Totowa, New Jersey.

Bonacci, T.M., Ghosh, M, Malik, S., and Smrcka, A.V. (2005) Regulatory interactions between the amino terminus of G-protein bg subunits and the catalytic domain of PLCb2. J Biol Chem 280:10174-10181.

Davis, T.L., Bonacci, T.M., Sprang, S.R., Smrcka, A.V. (2005) Structural and molecular characterization of a preferred protein interaction surface on G protein bg subunits. Biochemistry 44:10593-10604.

Malik, S., Ghosh, M., Bonacci, T.M., Tall, G.G., Smrcka, A.V. (2005) Ric-8 enhances G protein bg-dependent signaling in response to bg-binding peptides in intact cells. Mol. Pharmacol. 68: 129-36.

Wang, H., Oestreich, E.A., Maekawa, N., Bullard, T.A., Vikstrom, K.L., Dirksen, R.T., Kelley, G.G., Blaxall, B.C., and Smrcka, A.V. (2005) Phospholipase Ce modulates b-adrenergic receptor dependent cardiac contraction and inhibits cardiac hypertrophy. Circ. Res. 97:1305-1313.

Kelley, G.G., Kaproth-Joslin, K.A., Reks, S.E., Smrcka, A.V., Wojcikiewicz, J.H. (2006) G-protein coupled receptor agonists activate phospholipase Ce and phospholipase Cb3 in a temporally distinct manner. J. Biol. Chem. 281:2639-2648.

Mahon, M.J., Bonacci, T.M., Divieti, P., Smrcka, A.V. (2006) A docking site for G protein bg subunits on the parathyroid hormone1 receptor supports signaling through multiple pathways. Mol Endocrinol. 20:136-146.

Sato, M, Cismowski, M.J., Toyota, E., Smrcka, A.V., Lucchessi, P.A., Chilian, W.M., and Lanier, S.M. (2006) Identification of a receptor-independent activator of G-protein signaling (AGS8) in ischemic heart and its interaction with Gbg. Proc. Natl. Acad. Sci. USA. 103:797-802.

PubMed Publication List

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