title: Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels.
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.
authors.affiliation: Graduate Program in Biology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.forename: C
authors.initials: C
authors.lastname: Arrabit
authors.forename: S
authors.initials: S
authors.lastname: Choe
authors.forename: P A
authors.initials: PA
authors.lastname: Slesinger
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002045:Bupivacaine / Q000378:metabolism* / Q000494:pharmacology; D004594:Electrophysiology; D000431:Ethanol; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000779:Anesthetics, Local; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C086989:KCNJ1 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic; D000431:Ethanol; D020962:Heterotrimeric GTP-Binding Proteins; D002045:Bupivacaine