SUBUNIT-SPECIFIC INHIBITION OF INWARD-RECTIFIER K+ CHANNELS BY QUINIDINE

Distinct inward-rectifier K+ channel subunits were expressed in Xenopu s oocytes and tested for their sensitivity to the channel blocker quin idine, The 'strong' inward-rectifier K+ channel IRK1 was inhibited by quinidine with an EC, of 0.7 mM, while the 'weak' rectifier channel RO MK1 was only moderately inhibited. ROMK1(N171D)-IRK1(C-term) chimeric channels, which carry both sites for strong rectification of IRK1 chan nels (the negatively charged D171 in the second transmembrane domain a nd the IRK1-C-terminus including E224), displayed strong rectification like IRK1, but showed weak sensitivity to quinidine-like ROMK1, sugge sting independence of quinidine binding and rectification mechanisms, Moreover, BIR10 and BIR11, two strong rectifier subunits originally cl oned from rat brain, exerted subunit-specific sensitivity to quinidine , being much higher for BIR11, Quinidine blockade of IRK1 was not volt age-dependent, but strongly dependent on the pH in the superfusate, Th ese results strongly suggest a subunit-specific interaction of inward- rectifier K+ channels with neutral quinidine within membrane lipid bil ayers.