Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition

Abstract

human Ether-à-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K+ current (IKr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition. Accordingly, whole-cell patch-clamp measurements of hERG current (IhERG) were made at 37°C from hERG channels coexpressed with either wild-type (WT) KCNE1 or with one of three KCNE1 variants (A8V, D76N, and D85N). Under both conventional voltage clamp and ventricular action potential (AP) clamp, the amplitude of IhERG was smaller for A8V, D76N, and D85N KCNE1 + hERG than for WT KCNE1 + hERG. Using paired AP commands, with the second AP waveform applied at varying time intervals following the first to mimic premature ventricular excitation, the response of IhERG carried by each KCNE1 variant was reduced compared to that with WT KCNE1 + hERG. The IhERG blocking potency of the antiarrhythmic drug quinidine was similar between WT KCNE1 and the three KCNE1 variants. However, the IhERG inhibitory potency of the antibiotic clarithromycin and of the prokinetic drug cisapride was altered by KCNE1 variants. These results demonstrate that naturally occurring KCNE1 variants can reduce the response of hERG channels to premature excitation and also alter the sensitivity of hERG channels to inhibition by some drugs linked to acquired LQTS.

Modification of <i>KCNH2</i>-Encoded Cardiac Potassium Channels by KCNE1 Polymorphism

“…4 Our findings demonstrate that mutations to KCNE1 can influence hERG pharmacology for some but not all drugs. 4 Consequently, our recent study and that of Yamaguchi et al 1 independently provide mutually supportive evidence consistent with a potentially significant modulatory role of KCNE1 variants on hERG in relation to diLQTS. …”

“…Moreover, the 3 KCNE1 variants that we studied influenced the sensitivity of hERG to pharmacological blockade by 2 of 3 clinically used drugs that we investigated. 4 Thus, although hERG sensitivity to the Class Ia antiarrhythmic, quinidine, was similar between WT KCNE1 and the 3 mutant variants studied, that for the antibiotic clarithromycin and for the gastric prokinetic drug, cisapride, differed between the KCNE1 variants studied. 4 Our findings demonstrate that mutations to KCNE1 can influence hERG pharmacology for some but not all drugs.…”

“…4 Thus, although hERG sensitivity to the Class Ia antiarrhythmic, quinidine, was similar between WT KCNE1 and the 3 mutant variants studied, that for the antibiotic clarithromycin and for the gastric prokinetic drug, cisapride, differed between the KCNE1 variants studied. 4 Our findings demonstrate that mutations to KCNE1 can influence hERG pharmacology for some but not all drugs. 4 Consequently, our recent study and that of Yamaguchi et al 1 independently provide mutually supportive evidence consistent with a potentially significant modulatory role of KCNE1 variants on hERG in relation to diLQTS.…”

“…Nevertheless, we believe that these findings are potentially highly significant when considered alongside results of a recent study of ours in which the effects of 3 naturally occurring KCNE1 variants (A8V, D76N and D85N) on hERG current and pharmacology were investigated at physiological temperature. 4 Using both conventional voltage clamp and ventricular action potential voltage clamp, we found the magnitude of the hERG current to be markedly suppressed by each KCNE1 variant compared to wild-type (WT) KCNE1. Moreover, the 3 KCNE1 variants that we studied influenced the sensitivity of hERG to pharmacological blockade by 2 of 3 clinically used drugs that we investigated.…”

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

“…In most countries, and in particular in Europe, such history is very complicated and incompletely clarified. m.10398G was found associated with SZ in Han Chinese, however, when the cohort was broken down with respect to haplogroups, the association disappeared 24 . This illustrates that a specific allele's mtDNA haplogroup distribution may induce spurious association with SZ.…”