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Originally published In Press as doi:10.1074/jbc.M205325200 on October 25, 2002

J. Biol. Chem., Vol. 278, Issue 2, 1037-1043, January 10, 2003
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Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gbeta gamma Subunits*

Leif G. Hommers, Martin J. Lohse, and Moritz BünemannDagger

From the University of Würzburg, Department of Pharmacology & Toxicology, Versbacherstrasse 9, 97078 Würzburg, Germany

Gbeta gamma subunits are known to bind to and activate G-protein-activated inwardly rectifying K+ channels (GIRK) by regulating their open probability and bursting behavior. Studying G-protein regulation of either native GIRK (IKACh) channels in feline atrial myocytes or heterologously expressed GIRK1/4 channels in Chinese hamster ovary cells and HEK 293 cells uncovered a novel Gbeta gamma subunit mediated regulation of the inwardly rectifying properties of these channels. IKACh activated by submaximal concentrations of acetylcholine exhibited a ~2.5-fold stronger inward rectification than IKACh activated by saturating concentrations of acetylcholine. Similarly, the inward rectification of currents through GIRK1/4 channels expressed in HEK cells was substantially weakened upon maximal stimulation with co-expressed Gbeta gamma subunits. Analysis of the outward current block underlying inward rectification demonstrated that the fraction of instantaneously blocked channels was reduced when Gbeta gamma was over-expressed. The Gbeta gamma induced weakening of inward rectification was associated with reduced potencies for Ba2+ and Cs+ to block channels from the extracellular side. Based on these results we propose that saturation of the channel with Gbeta gamma leads to a conformational change within the pore of the channel that reduced the potency of extracellular cations to block the pore and increased the fraction of channels inert to a pore block in outward direction.

* This work was supported by Deutsche Forschungsgemeinschaft Research Fellowship BU 1133/1 (to M. B.) and a Leibniz award (to M. J. L.).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.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, University of Würzburg, Versbacherstrasse 9, 97078 Würzburg, Germany. Tel.: 49-931-201-48854; Fax: 49-931-201-48539; E-mail: m-buenemann@toxi.uni-wuerzburg.de.

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