Modulation of homomeric and heteromeric KCNQ1 channels by external acidification.
The I(KS) K(+) channel plays a major role in repolarizing the cardiac action potential. It consists of an assembly of two structurally distinct alpha and beta subunits called KCNQ1 and KCNE1, respectively. Using two different expression systems, Xenopus oocytes and Chinese hamster ovary cells, we investigated the effects of external protons on homomeric and heteromeric KCNQ1 channels. External acidification (from pH 7.4 to pH 5.5) markedly decreased the homomeric KCNQ1 current amplitude and caused a positive shift (+25 mV) in the voltage dependence of activation. Low external pH (pH(o)) also slowed down the activation and deactivation kinetics and strongly reduced the KCNQ1 inactivation process. In contrast, external acidification reduced the maximum conductance and the macroscopic inactivation of the KCNQ1 mutant L273F by only a small amount. The heteromeric I(KS) channel complex was weakly affected by low pH(o), with minor effects on I(KS) current amplitude. However, substantial current inhibition was produced by protons with the N-terminal KCNE1 deletion mutant Delta11-38. Low pH(o) increased the current amplitude of the pore mutant V319C when co-expressed with KCNE1. The slowing of I(KS) deactivation produced by low pH(o) was absent in the KCNE1 mutant Delta39-43, suggesting that the residues lying at the N-terminal boundary of the transmembrane segment are involved in this process. In all, our results suggest that external acidification acts on homomeric and heteromeric KCNQ1 channels via multiple mechanisms to affect gating and maximum conductance. The external pH effects on I(Kr) versus I(KS) may be important determinants of arrhythmogenicity under conditions of cardiac ischaemia and reperfusion.
Peretz
Asher
A
Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel.
Schottelndreier
Hella
H
Aharon-Shamgar
Liora Ben
LB
Attali
Bernard
B
D000143:Acids / Q000494:pharmacology*; D000818:Animals; D004553:Electric Conductivity; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D007700:Kinetics; D009154:Mutation; D009865:Oocytes; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013997:Time Factors; D014982:Xenopus laevis
D000143:Acids; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)