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J. Biol. Chem., Vol. 281, Issue 45, 34549-34560, November 10, 2006

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RGS3 and RGS4 Differentially Associate with G Protein-coupled Receptor-Kir3 Channel Signaling Complexes Revealing Two Modes of RGS Modulation

PRECOUPLING AND COLLISION COUPLING^*

From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida 33612

RGS3 and RGS4 are GTPase-activating proteins expressed in the brain and heart that accelerate the termination of G_i/o- and G_q-mediated signaling. We report here the determinants mediating selective association of RGS4 with several G protein-coupled receptors (GPCRs) that form macromolecular complexes with neuronal G protein-gated inwardly rectifying potassium (Kir3 or GIRK) channels. Kir3 channels are instrumental in regulating neuronal firing in the central and peripheral nervous system and pacemaker activity in the heart. By using an epitope-tagged degradation-resistant RGS4 mutant, RGS4(C2V), immunoprecipitation of several hemagglutinin-tagged G_i/o-coupled and G_q-coupled receptors expressed in Chinese hamster ovary (CHO-K1) cells readily co-precipitated both Kir3.1/Kir3.2a channels and RGS4(C2V). In contrast to RGS4(C2V), the closely related and functionally active RGS3 "short" isoform (RGS3s) did not interact with any of the GPCR-Kir3 channel complexes examined. Deletion and chimeric RGS constructs indicate both the N-terminal domain and the RGS domain of RGS4(C2V) are necessary for association with m2 receptor-Kir3.1/Kir3.2a channel complexes, where the GPCR was found to be the major target for RGS4(C2V) interaction. The functional impact of RGS4(C2V) "precoupling" to the GPCR-Kir3 channel complex versus RGS3s "collision coupling" was a 100-fold greater potency in the acceleration of G protein-dependent Kir3 channel-gating kinetics with no attenuation in current amplitude. These findings demonstrate that RGS4, a highly regulated modulator and susceptibility gene for schizophrenia, can directly associate with multiple GPCR-Kir3 channel complexes and may affect a wide range of neurotransmitter-mediated inhibitory and excitatory events in the nervous and cardiovascular systems.

Received for publication, April 4, 2006 , and in revised form, August 17, 2006.

^* This work was supported by a grant-in-aid from the American Heart Association (Florida and Puerto Rico Affiliate) and an Institutional Research Grant from the American Cancer Society (H. Lee Moffitt Cancer Center & Research Institute). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC8, Tampa, FL 33612. Tel.: 813-974-1557; Fax: 813-974-3079; E-mail: cdoupnik{at}health.usf.edu.

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