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J. Biol. Chem., Vol. 280, Issue 17, 16685-16694, April 29, 2005

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G-dependent and G-independent Basal Activity of G Protein-activated K⁺ Channels^*

Ida Rishal, Yuri Porozov, Daniel Yakubovich, Dalia Varon, and Nathan Dascal

From the Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

Cardiac and neuronal G protein-activated K⁺ channels (GIRK; Kir3) open following the binding of G subunits, released from G_i/o proteins activated by neurotransmitters. GIRKs also possess basal activity contributing to the resting potential in neurons. It appears to depend largely on free G, but a G-independent component has also been envisaged. We investigated G dependence of the basal GIRK activity (A_GIRK,basal) quantitatively, by titrated expression of G scavengers, in Xenopus oocytes expressing GIRK1/2 channels and muscarinic m2 receptors. The widely used G scavenger, myristoylated C terminus of -adrenergic kinase (m-cARK), reduced A_GIRK,basal by 70–80% and eliminated the acetylcholine-evoked current (I_ACh). However, we found that m-cARK directly binds to GIRK, complicating the interpretation of physiological data. Among several newly constructed G scavengers, phosducin with an added myristoylation signal (m-phosducin) was most efficient in reducing GIRK currents. m-phosducin relocated to the membrane fraction and did not bind GIRK. Titrated expression of m-phosducin caused a reduction of A_GIRK,basal by up to 90%. Expression of GIRK was accompanied by an increase in the level of G and G in the plasma membrane, supporting the existence of preformed complexes of GIRK with G protein subunits. Increased expression of G and its constitutive association with GIRK may underlie the excessively high A_GIRK,basal observed at high expression levels of GIRK. Only 10–15% of A_GIRK,basal persisted upon expression of both m-phosducin and cARK. These results demonstrate that a major part of I_basal is G-dependent at all levels of channel expression, and only a small fraction (<10%) may be G-independent.

Received for publication, October 27, 2004 , and in revised form, February 22, 2005.

^* This work was supported by National Institutes of Health Grant RO1 GM68493 and USA-Israel Binational Science Foundation Grant 2001-122. 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: Dept. of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. Tel.: 972-3-6405743; Fax: 972-3-6409113; E-mail: dascaln{at}post.tau.ac.il.

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