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

Abstract

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’ 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.