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.