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RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K^+ channels

Doupnik, Craig A. and Davidson, Norman and Lester, Henry A. and Kofuji, Paulo (1997) RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K^+ channels. Proceedings of the National Academy of Sciences of the United States of America, 94 (19). pp. 10461-10466. ISSN 0027-8424. PMCID PMC23385.

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G protein gated inward rectifier K+ (GIRK) channels mediate hyperpolarizing postsynaptic potentials in the nervous system and in the heart during activation of G alpha(i/o) coupled receptors. In neurons and cardiac atrial cells the time course for receptor-mediated GIRK current deactivation is 20-40 times faster than that observed in heterologous systems expressing cloned receptors and GIRK channels, suggesting that an additional component(s) is required to confer the rapid kinetic properties of the native transduction pathway. We report here that heterologous expression of "regulators of G protein signaling" (RGS proteins), along with cloned G protein-coupled receptors and GIRK channels, reconstitutes the temporal properties of the native receptor --> GIRK signal transduction pathway. GIRK current waveforms evoked by agonist activation of muscarinic m(2) receptors or serotonin 1A receptors were dramatically accelerated by coexpression of either RGS1, RGS3, or RGS4, but not RGS2. For the brain-expressed RGS4 isoform, neither the current amplitude nor the steady-state agonist dose-response relationship was significantly affected by RGS expression, although the agonist-independent "basal" GIRK current was suppressed by approximate to 40%. Because GIRK activation and deactivation kinetics are the limiting rates for the onset and termination of "slow" postsynaptic inhibitory currents in neurons and atrial cells, RGS proteins may play crucial roles in the timing of information transfer within the brain and to peripheral tissues.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1997 by the National Academy of Sciences. Contributed by Norman Davidson, July 17, 1997. We thank Drs. Kirk Druey and John Kehrl for providing RGS1–3 cDNAs, Brad Henkle and Hai-Rong Li for preparing oocytes, and Dr. Mark Jasek for helping with the mammalian cell transfection procedures. This work was supported by fellowships from the American Heart Association (C.A.D. and P.K.) and the Guenther Foundation (P.K.), and by grants from the National Institutes of Health and the National Institute of Mental Health. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
American Heart AssociationUNSPECIFIED
Guenther FoundationUNSPECIFIED
National Institute of Mental Health (NIMH)UNSPECIFIED
Issue or Number:19
PubMed Central ID:PMC23385
Record Number:CaltechAUTHORS:DOUpnas97
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:915
Deposited By: Tony Diaz
Deposited On:08 Nov 2005
Last Modified:02 Oct 2019 22:38

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