Acidosis impairs the protective role of hERG K(+) channels against premature stimulation.
BACKGROUND
Potassium channels encoded by human ether-à-go-go-related gene (hERG) underlie the cardiac rapid delayed rectifier K(+) channel current (I(Kr)). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including I(Kr) . The aim of this study was to characterize effects of extracellular acidosis on hERG current (I(hERG)), with particular reference to quantifying effects on I(hERG) elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli.


RESULTS
I(hERG) recordings were made from hERG-expressing Chinese Hamster Ovary cells using whole-cell patch-clamp at 37°C. I(hERG) during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state I(hERG) activation were shifted by ∼+6 mV; maximal I(hERG) conductance was reduced. The voltage-dependence of I(hERG) inactivation was little-altered. Fast and slow time-constants of I(hERG) deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time-course of recovery of I(hERG) from inactivation was observed, but time-course of activation was unaffected. The amplitude of outward I(hERG) transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3.


CONCLUSIONS
During acidosis the contribution of I(hERG) to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli.
Du
Chun Yun
CY
Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, Bristol, UK.
Adeniran
Ismail
I
Cheng
Hongwei
H
Zhang
Yi Hong
YH
El Harchi
Aziza
A
McPate
Mark J
MJ
Zhang
Henggui
H
Orchard
Clive H
CH
Hancox
Jules C
JC
D000138:Acidosis / Q000503:physiopathology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D018408:Patch-Clamp Techniques
D051638:Ether-A-Go-Go Potassium Channels