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First published on September 29, 2006; DOI: 10.1124/mol.106.028670

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Received for publication July 11, 2006.
Revised September 19, 2006.
Accepted for publication September 27, 2006.

Identification of small molecule inhibitors of Regulator of G-protein Signaling 4 (RGS4) using a high throughput flow cytometry protein interaction assay (FCPIA)

David L. Roman 1, Jeffery N. Talbot 1, Rebecca A. Roof 1, Roger K. Sunahara 1, John R. Traynor 1, Richard R. Neubig 1*

1 University of Michigan Medical School

* Address correspondence to: E-mail: rneubig{at}umich.edu

Abstract

Regulators of G-protein signaling (RGS) proteins are important components of signal transduction pathways initiated through G-protein coupled receptors (GPCRs). RGS proteins accelerate the intrinsic GTPase activity of G-protein {alpha}-subunits (G{alpha}) and thus shorten the time course and reduce the magnitude of G-protein {alpha} and {beta}{gamma} subunit signaling. Inhibiting RGS action has been proposed as a means to enhance the activity and specificity of GPCR agonist drugs but pharmacological targeting of protein-protein interactions has typically been difficult. The aim of this project was to identify inhibitors of RGS4. Using a Luminex® 96-well-plate bead analyzer and a novel flow-cytometric protein interaction assay (FCPIA) to assess G{alpha}-RGS interactions in a high-throughput screen, we identified the first small molecule inhibitor of an RGS protein. Of 3028 compounds screened, one, CCG- 4986, inhibited RGS4/G{alpha}o binding with 3-5 µM potency. It binds to RGS4, inhibits RGS4 stimulation of G{alpha}o GTPase activity in vitro, and prevents RGS4 regulation of µ-opioid inhibited adenylyl cyclase activity in permeablized cells. Furthermore, CCG-4986 is selective for RGS4 and does not inhibit RGS8. Thus we demonstrate the feasibility of targeting RGS/G{alpha} protein-protein interactions with small molecules as a novel means to modulate GPCR-mediated signaling processes.


Key words: G protein regulation, RGS proteins, Fluorescence techniques


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