Subunit-specific inhibition of inward-rectifier K + channels by quinidine

• Published in: FEBS letters Vol. 375; no. 3; pp. 193 - 196
• Main Authors: Doi, T., Fakler, B., Schultz, J.H., Ehmke, H., Brändle, U., Zenner, H.-P., Süßbrich, H., Lang, F., Ruppersberg, J.P., Busch, A.E.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 20.11.1995
• Subjects: Animals; Base Sequence; Brain - physiology; Cloning, Molecular; DNA Primers; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Inward rectifier K + channel; Macromolecular Substances; Membrane Potentials - drug effects; Molecular Sequence Data; Mutagenesis; Oocytes - drug effects; Oocytes - physiology; Polymerase Chain Reaction; Potassium Channel Blockers; Potassium Channels - biosynthesis; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying; Quinidine; Quinidine - pharmacology; Rats; Recombinant Fusion Proteins - antagonists & inhibitors; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - biosynthesis; Recombinant Proteins - metabolism; Xenopus; pH; Inward rectifier K + channel; Quinidine
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(95)01182-E

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 EC 50 of 0.7 mM, while the ‘weak’ reactifier channel ROMK1 was only moderately inhibited. ROMK1(N171D)-IRKI C-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.