NDLI: Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying $K^{+}$ channels

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Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying $K^{+}$ channels

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Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying $K^{+}$ channels

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Arrabit, C. Slesinger, P. A. Zhou, W. Choe, S.
Description	Author Affiliation: Zhou W ( Graduate Program in Biology, University of California at San Diego, La Jolla, CA 92093, USA.);
Abstract	Local anesthetics, commonly used for treating cardiac arrhythmias, pain, and seizures, are best known for their inhibitory effects on voltage-gated Na(+) channels. Cardiovascular and central nervous system toxicity are unwanted side-effects from local anesthetics that cannot be attributed to the inhibition of only Na(+) channels. Here, we report that extracellular application of the membrane-permeant local anesthetic bupivacaine selectively inhibited G protein-gated inwardly rectifying K(+) channels (GIRK:Kir3) but not other families of inwardly rectifying K(+) channels (ROMK:Kir1 and IRK:Kir2). Bupivacaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directly via coexpressed G protein G(beta)gamma subunits. Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive G proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels containing the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP(2)) domain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP(2) were inhibited by ethanol, like IRK1 channels. We propose that membrane-permeant local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP(2) with the channel, which is essential for G(beta)gamma and ethanol activation of GIRK channels.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	11
Volume Number	98
Language	English
Publisher	National Academy of Sciences
Publisher Date	2001-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Anesthetics, Local Metabolism Bupivacaine GTP-Binding Protein Beta Subunits GTP-Binding Protein Gamma Subunits Heterotrimeric GTP-Binding Proteins Potassium Channel Blockers Potassium Channels, Inwardly Rectifying Receptors, Muscarinic Pharmacology Animals Electrophysiology Ethanol G Protein-Coupled Inwardly-Rectifying Potassium Channels Phosphatidylinositol 4,5-Diphosphate Potassium Channels Genetics Physiology Xenopus Laevis Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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