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J. Biol. Chem. 278 (6): 3840-3845

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Na+ Promotes the Dissociation between Galpha GDP and Gbeta gamma , Activating G Protein-gated K+ Channels*

Ida Rishal, Tal Keren-RaifmanDagger , Daniel Yakubovich, Tatiana Ivanina, Carmen W. Dessauer§, Vladlen Z. SlepakDagger , and Nathan Dascal

From the Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel, the Dagger  Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33156, and the § Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, Texas 77030

G protein-gated K+ channels (GIRK, or Kir3) are activated by the direct binding of Gbeta gamma or of cytosolic Na+. Na+ activation is fast, Gbeta gamma -independent, and probably via a direct, low affinity (EC50, 30-40 mM) binding of Na+ to the channel. Here we demonstrate that an increase in intracellular Na+ concentration, [Na+]in, within the physiological range (5-20 mM), activates GIRK within minutes via an additional, slow mechanism. The slow activation is observed in GIRK mutants lacking the direct Na+ effect. It is inhibited by a Gbeta gamma scavenger, hence it is Gbeta gamma -dependent; but it does not require GTP. We hypothesized that Na+ elevates the cellular concentration of free Gbeta gamma by promoting the dissociation of the Galpha beta gamma heterotrimer into free Galpha GDP and Gbeta gamma . Direct biochemical measurements showed that Na+ causes a moderate decrease (~2-fold) in the affinity of interaction between Galpha GDP and Gbeta gamma . Furthermore, in accord with the predictions of our model, slow Na+ activation was enhanced by mild coexpression of Galpha i3. Our findings reveal a previously unknown mechanism of regulation of G proteins and demonstrate a novel Gbeta gamma -dependent regulation of GIRK by Na+. We propose that Na+ may act as a regulatory factor, or even a second messenger, that regulates effectors via Gbeta gamma .

* This work was supported by National Institutes of Health Grants GM56260 (to N. D.), GM60419 (to C. D.), and GM60019 (to V. S.) and grants from the United States-Israel Binational Science Foundation (to N. D., V. S., and C. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 972-3-6405743; Fax: 972-3-6409113; E-mail:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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