Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels

Citation
W. Zhou et al., Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels, P NAS US, 98(11), 2001, pp. 6482-6487
Citations number
55
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
0027-8424 → ACNP
Volume
98
Issue
11
Year of publication
2001
Pages
6482 - 6487
Database
ISI
SICI code
0027-8424(20010522)98:11<6482:MUBIOG>2.0.ZU;2-8
Abstract
Local anesthetics, commonly used for treating cardiac arrhythmias, pain, an d 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 inhib ition 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). Bupiv acaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directl y via coexpressed G protein G(beta gamma) subunits. Bupivacaine also inhibi ted alcohol-induced GIRK currents in the absence of functional pertussis to xin-sensitive C proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels co ntaining the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP2) dom ain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP2 wer e inhibited by ethanol, like IRK1 channels. We propose that membrane-permea nt local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP2 with the channel, which is essential for G(beta gamma) and ethanol activation of GIRK channels.