Suppression of the hERG potassium channel response to premature stimulation by reduction in extracellular potassium concentration

Potassium channels encoded by human ether‐à‐go‐go‐related gene ( hERG ) mediate the cardiac rapid delayed rectifier K + current ( I Kr ), which participates in ventricular repolarization and has a protective role against unwanted premature stimuli late in repolarization and early in diastole. Ionic current carried by hERG channels ( I hERG ) is known to exhibit a paradoxical dependence on external potassium concentration ([K + ] e ), but effects of acute [K + ] e changes on the response of I hERG to premature stimulation have not been characterized. Whole‐cell patch‐clamp measurements of hERG current were made at 37°C from hERG channels expressed in HEK293 cells. Under conventional voltage‐clamp, both wild‐type (WT) and S624A pore‐mutant I hERG during depolarization to +20 mV and subsequent repolarization to −40 mV were decreased when superfusate [K + ] e was decreased from 4 to 1 mmol/L. When [K + ] e was increased from 4 to 10 mmol/L, pulse current was increased and tail I hERG was decreased. Increasing [K + ] e produced a +10 mV shift in voltage‐dependent inactivation of WT I hERG and slowed inactivation time course, while lowering [K + ] e from 4 to 1 mmol/L produced little change in inactivation voltage dependence, but accelerated inactivation time course. Under action potential (AP) voltage‐clamp, lowering [K + ] e reduced the amplitude of I hERG during the AP and suppressed the maximal I hERG response to premature stimuli. Raising [K + ] e increased I hERG early during the AP and augmented the I hERG response to premature stimuli. Our results are suggestive that during hypokalemia not only is the contribution of I Kr to ventricular repolarization reduced but its ability to protect against unwanted premature stimuli also becomes impaired.