Subunit-specific inhibition of inward-rectifier K+ channels by quinidine.
Distinct inward-rectifier K+ channel subunits were expressed in Xenopus oocytes and tested for their sensitivity to the channel blocker quinidine. The 'strong' inward-rectifier K+ channel IRK1 was inhibited by quinidine with an EC50 of 0.7 mM, while the 'weak' rectifier channel ROMK1 was only moderately inhibited. ROMK1(N171D)-IRK1C-term chimeric channels, which carry both sites for strong rectification of IRK1 channels (the negatively charged D171 in the second transmembrane domain and the IRK1-C-terminus including E224), displayed strong rectification like IRK1, but showed weak sensitivity to quinidine-like ROMK1, suggesting independence of quinidine binding and rectification mechanisms. Moreover, BIR10 and BIR11, two strong rectifier subunits originally cloned from rat brain, exerted subunit-specific sensitivity to quinidine, being much higher for BIR11. Quinidine blockade of IRK1 was not voltage-dependent, but strongly dependent on the pH in the superfusate. These results strongly suggest a subunit-specific interaction of inward-rectifier K+ channels with neutral quinidine within membrane lipid bilayers.
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000502:physiology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000096:biosynthesis / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014981:Xenopus
D017931:DNA Primers; D046911:Macromolecular Substances; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D011802:Quinidine