Abstract

Modulating Regulators of G Protein Signalling – A Therapeutic Challenge

Richard Neubig, Professor and Chair, Michigan State University

Regulators of G protein signalling (RGS) proteins bind to active G proteins of the Gi and Gq families and suppress receptor signalling. Zhong and Neubig (JPET, 2000) proposed that RGS proteins could provide a novel therapeutic approach to enhance the efficacy and specificity of GPCR agonist signalling. Recent studies have implicated a role for RGS4 in the effects of dopamine in Parkinson’s. RGS4 knock-out mice appear to bypass the requirement for dopamine suggesting that RGS4 inhibitors could substitute for the dopamine lost through nigral neurodegeneration. We have identified a novel series of RGS4 inhibitors with in vivo activity. They work through a unique mechanism dependent on RGS4 protein dynamics. Insights into the feasibility of targeting RGS proteins and recent results from in vivo studies will be presented.