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Originally published In Press as doi:10.1074/jbc.M211461200 on December 25, 2002

J. Biol. Chem., Vol. 278, Issue 9, 7091-7098, February 28, 2003
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Inhibition of G-protein-coupled Inward Rectifying K+ Channels by Intracellular Acidosis*

Jinzhe Mao, Jianping Wu, Fuxue Chen, Xueren Wang, and Chun JiangDagger

From the Department of Biology, Georgia State University, Atlanta, Georgia 30302-4010

G-protein-coupled inward rectification K+ (GIRK) channels play an important role in modulation of synaptic transmission and cellular excitability. The GIRK channels are regulated by diverse intra- and extracellular signaling molecules. Previously, we have shown that GIRK1/GIRK4 channels are activated by extracellular protons. The channel activation depends on a histidine residue in the M1-H5 linker and may play a role in neurotransmission. Here, we show evidence that the heteromeric GIRK1/GIRK4 channels are inhibited by intracellular acidification. This inhibition was produced by selective decrease in the channel open probability with a modest drop in the single-channel conductance. The inhibition does not seem to require G-proteins as it was seen in two G-protein coupling-defective GIRK mutants and in excised patches in the absence of exogenous G-proteins. Three histidine residues in intracellular domains were critical for the inhibition. Individual mutation of His-64, His-228, or His-352 in GIRK4 abolished or greatly diminished the inhibition in homomeric GIRK4. Mutations of any of these histidine residues in GIRK4 or their counterparts in GIRK1 were sufficient to eliminate the pHi sensitivity of the heteromeric GIRK1/GIRK4 channels. Thus, the molecular and biophysical bases for the inhibition of GIRK channels by intracellular protons are illustrated. Because of the inequality of the pHi and pHo in most cells and their relatively independent controls by cellular versus systemic mechanisms, such pHi sensitivity may allow these channels to regulate cellular excitability in certain physiological and pathophysiological conditions when intracellular acidosis occurs.

* This work was supported by the National Institutes of Health (Grant HL58410) and by the American Diabetes Association (Grant 1-01-RA-12).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 A Career Investigator of the American Lung Association. To whom correspondence should be addressed: Dept. of Biology, Georgia State University, 24 Peachtree Center Ave., Atlanta, GA 30302-4010. Tel.: 404-651-0913; Fax: 404-651-2509; E-mail: cjiang@gsu.edu.

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