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J. Biol. Chem., Vol. 279, Issue 17, 17260-17268, April 23, 2004

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G_i1 and G_i3 Differentially Interact with, and Regulate, the G Protein-activated K⁺ Channel^*

Tatiana Ivanina, Dalia Varon, Sagit Peleg, Ida Rishal, Yuri Porozov, Carmen W. Dessauer, Tal Keren-Raifman, and Nathan Dascal¶

From the Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel and the Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, Texas 77030

G protein-activated K⁺ channels (GIRKs; Kir3) are activated by direct binding of G subunits released from heterotrimeric G proteins. In native tissues, only pertussis toxin-sensitive G proteins of the G_i/o family, preferably G_i3 and G_i2, are donors of G for GIRK. How this specificity is achieved is not known. Here, using a pull-down method, we confirmed the presence of G_i3-GDP binding site in the N terminus of GIRK1 and identified novel binding sites in the N terminus of GIRK2 and in the C termini of GIRK1 and GIRK2. The non-hydrolyzable GTP analog, guanosine 5'-3-O-(thio)triphosphate, reduced the binding of G_i3 by a factor of 2–4. G_i1-GDP bound to GIRK1 and GIRK2 much weaker than G_i3-GDP. Titrated expression of components of signaling pathway in Xenopus oocytes and their activation by m2 muscarinic receptors revealed that G_i3 activates GIRK more efficiently than G_i1, as indicated by larger and faster agonist-evoked currents. Activation of GIRK by purified G in excised membrane patches was strongly augmented by coexpression of G_i3 and less by G_i1. Differences in physical interactions of GIRK with GDP-bound G subunits, or G heterotrimers, may dictate different extents of G anchoring, influence the efficiency of GIRK activation by G, and play a role in determining signaling specificity.

Received for publication, December 9, 2003 , and in revised form, February 3, 2004.

^* This work was supported by National Institutes of Health Grants GM60419 (to C. D.) and GM68493 (to N. D.) and by the USA-Israel Binational Science Foundation (to N. D. and C. D.). 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.

^¶ To whom correspondence should be addressed: Tel.: 972-3-640-5743; Fax: 972-3-640-9113; E-mail: dascaln{at}post.tau.ac.il.

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