Faculty

Our laboratory is primarily interested in the biochemical dissection of members of this pathway and correlation of the structural and functional consequences of signal activation and propagation. We address fundamental aspects of the G Protein-Coupled Receptor (GPCR) signaling cascades and have used the study of G proteins and the soluble portion of adenylyl cyclase as a model system. In previous studies we utilized several approaches to study the behavior of G proteins on regulation of adenylyl cyclase.

The atomic structures of thousands of cytosolic proteins together with a plethora of functional data have provided a firm understanding of how these proteins work. Unfortunately very few membrane protein structures have been resolved. The structure of only one GPCR, bovine rhodopsin, has been elucidated thus far. Although it represents a monumental achievement, the X-ray structure revealed only slightly more than previously predicted by electron microscopy and other biophysical studies. The question of how light-induced isomerization of the chromaphore results in G protein activation remains largely unresolved.

The need to understand the underlying mechanism of GPCR signaling is underscored by the fact that the majority of all therapeutics target GPCR signaling cascades (~ 60% of all pharmaceutics). Genome projects have introduced novel potential therapeutic targets by uncovering hundreds of novel GPCRs, new G proteins and effectors. A firm understanding of the mechanism of signaling events will help the development of more potent and more selective therapeutics.

High-resolution structural and functional characterization of GPCRs themselves will undoubtedly facilitate such goals. For example, knowledge of the three-dimensional structure of co-receptors for HIV, also GPCRs, could lead to the development of selective drugs that block HIV infection. A beta-adrenergic receptor structure will aid in the development of more selective and potent cardiovascular therapeutics.

Most neuroleptics that target dopamine receptors, also GPCRs, have been successfully used for the treatment of schizophrenia, Huntington's Chorea and Parkinson's Syndrome. The development of more selective dopamine receptor ligands, with reduced side-effects, will improve drug efficacy, improve drug compliance and most of all improve the quality of life during treatment.

Representative Publications

1. Klein, C., Sunahara, R.K., Hudson, T.Y., Heyduk, T. and Howlett, A.C., "Zinc Inhibition of cAMP Signalling", J. Biol. Chem., 2002.

2. Tesmer, J.J., Sunahara, R.K., Fancy, D.A., Gilman, A.G. and Sprang, S.R., "Crystallization of Complex between Soluble Domains of Adenylyl Cyclase and Activated Gs Alpha", Methods Enzymol., 2002, 345, 198.

3. Hatley, M.E., Gilman, A.G. and Sunahara, R.K., "Expression, Purification, and Assay of Cytosolic (catalytic) Domains of Membrane-bound Mammalian Adenylyl Cyclases", Methods Enzymol., 2002, 345, 127.

4. Wang, L., Sunahara, R.K., Krumins, A., Perkins, G., Crochiere, M.L., Mackey, M., Bell, S., Ellisman, M.H. and Taylor, S.S., "Cloning and Mitochondrial Localization of Full-length D-AKAP2, a Protein Kinase A Anchoring Protein", Proc. Natl. Acad. Sci. USA, 2001, 98(6), 3220.

5. Tesmer, J.J., Dessauer, C.W., Sunahara, R.K., Murray, L.D., Johnson, R.A., Gilman, A.G. and Sprang, S.R., "Molecular Basis for P-site Inhibition of Adenylyl Cyclase", Biochemistry, 2000, 39(47), 14464.