期刊
MOLECULAR PHARMACOLOGY
卷 71, 期 1, 页码 169-175出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.106.028670
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资金
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM076821] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA007268, R01DA004087] Funding Source: NIH RePORTER
- NIDA NIH HHS [DA004087, T32-DA007268] Funding Source: Medline
- NIGMS NIH HHS [F32-GM076821, GM039561] Funding Source: Medline
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 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, 1, methyl N-[(4-chlorophenyl) sulfonyl]-4-nitrobenzenesulfinimidoate (CCG-4986), inhibited RGS4/ G alpha(o) binding with 3 to 5 mu M potency. It binds to RGS4, inhibits RGS4 stimulation of G alpha(o) GTPase activity in vitro, and prevents RGS4 regulation of mu-opioid-inhibited adenylyl cyclase activity in permeabilized 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.
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