KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degreesC to 20 degreesC increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (I-Ks) but by only twofold (not significant) for KCNQ1 currents (I-K) in CHO cells. Acidification of cytosolic pH (pH(i)) increased I-Ks but decreased I-K whereas intracellular alkalinization decreased I-Ks but increased I-K.(.) pH(i)-induced changes in intracellular Ca2+ activity ([Ca2+](i)) did not correlate with the current responses. At 20 degreesC mefenamic acid (0.1 nM) significantly augmented I-Ks but slightly decreased I-K. It changed the slow activation kinetics of I-Ks to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degreesC, mefenamic acid also increased I-Ks but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I-Ks with a lower potency than I-K. These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pH(i). In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I-Ks might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.