We study the regulation of G protein coupled receptors (GPCRs) which form the largest family of cell surface receptors and are the targets for about half of all known drugs.
Proteins called regulators of G protein signaling (RGS) are important modulators of GPCR signaling pathways. We have been studying an RGS family member, RGS9-2, whose expression is highly enriched in the striatum, a brain region that is important in the control of movement and is also associated with reward responses. A major input into the striatum consists of dopaminergic neurons and we have shown that RGS9-2 specifically regulates striatal D2-dopamine receptors and plays a role in the development of the locomotor side-effects of drugs that are used to treat schizophrenia and Parkinson's disease. These drugs are either antagonists or activators of D2-dopamine receptors, respectively, and treatment with these drugs can produce locomotor side-effects due to the drug-mediated modulation of D2-dopamine receptors in the striatum.
More recently we have demonstrated in a human population and using rat and mice models that RGS9 2 is a regulator of body weight and adiposity.
The lab is presently is studying the actions of RGS9-2 at the cellular level and in particular investigating how RGS9-2 regulates dopaminergic signal so as to better understand the brain mechanisms underlying the control of body-weight and the locomotor side-effects of psychoactive drugs.
Waugh J. L., Celver J., Sharma M., Dufresne R. L., Terzi D., Risch S.C., Fairbrother W.G., Neve R.L., Kane J.P., Malloy M.J., Pullinger C.R., Gu H.F., Tsatsanis C., Hamilton S.P., Gold S. J., Zachariou V., Kovoor A. (2011) Association Between Regulator of G Protein Signaling 9-2 and Body Weight. PLoS One (in press)
Celver J., Sharma M. and Kovoor A. (2011) D2-Dopamine Receptors Target Regulator of G Protein Signaling 9-2 (RGS9-2) to Detergent-Resistant Membrane Fractions. J Neurochem. (in press)
Sharma M., Celver J. and Kovoor A. (2011) Regulator of G protein signaling 9-2 (RGS9-2) mRNA is up regulated during neuronal differentiation of mouse embryonic stem cells. Neurosci Lett 502, 123-128.
Celver J., Sharma M. and Kovoor A. (2010) RGS9-2 mediates specific inhibition of agonist-induced internalization of D2-dopamine receptors. J Neurochem 114, 739-749.
Masuho I., Celver J., Kovoor A. and Martemyanov K. A. (2010) Membrane anchor R9AP potentiates GTPase-accelerating protein activity of RGS11 x Gbeta5 complex and accelerates inactivation of the mGluR6-G(o) signaling. J Biol Chem 285, 4781-4787.
Kovoor A., Seyffarth P., Ebert J., Barghshoon S., Chen C. K., Schwarz S., Axelrod J. D., Cheyette B. N., Simon M. I., Lester H. A. and Schwarz J. (2005) D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. J Neurosci 25, 2157-2165.
Rahman Z., Schwarz J., Gold S. J., Zachariou V., Wein M. N., Choi K. H., Kovoor A., Chen C. K., DiLeone R. J., Schwarz S. C., Selley D. E., Sim-Selley L. J., Barrot M., Luedtke R. R., Self D., Neve R. L., Lester H. A., Simon M. I. and Nestler E. J. (2003) RGS9 modulates dopamine signaling in the basal ganglia. Neuron 38, 941-952.
Kovoor A., Chen C. K., He W., Wensel T. G., Simon M. I. and Lester H. A. (2000) Co-expression of Gbeta5 enhances the function of two Ggamma subunit-like domain-containing regulators of G protein signaling proteins. J Biol Chem 275, 3397-3402.