Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles.

backgroundMutations in the KCNQ1 and human ether-a-go-go-related gene (HERG) genes cause the long QT syndromes, LQTS1 and LQTS2, due to reductions in the cardiac repolarizing I(Ks) and I(Kr) currents, respectively. It was previously reported that KCNQ1 coexpression modulates HERG function by enhancing membrane expression of HERG, and that the 2 proteins coimmunoprecipitate, and colocalize in myocytes. In vivo studies in genetically modified rabbits also support a HERG-KCNQ1 interaction.

objectiveWe sought to determine whether KCNQ1 influences the current characteristics of HERG genetic variants.

methodsThis study used expression of HERG and KCNQ1 wild-type (WT) and mutant channels in heterologous systems, combined with whole-cell patch clamp analysis and biochemistry.

resultsSupporting the notion that KCNQ1 needs to be trafficking competent to influence HERG function, we found that although the tail current density of HERG expressed in Chinese Hamster Ovary (CHO) cells was approximately doubled by WT KCNQ1 coexpression, it was not altered in the presence of the trafficking-defective KCNQ1(T587M) variant. Activation and deactivation kinetics of HERG variants were not altered. The HERG(M124T) variant, previously shown to be mildly impaired functionally, was restored to WT levels by KCNQ1-WT but not KCNQ1(T587M) coexpression. The tail current densities of the severely trafficking-impaired HERG(G601S) and HERG(F805C) variants were only slightly improved by KCNQ1 coexpression. The trafficking competent but incompletely processed HERG(N598Q), and a mutation in the selectivity filter, HERG(G628S), were not improved by KCNQ1 coexpression.

conclusionThese findings suggest a functional codependence of HERG on KCNQ1 during channel biogenesis. Moreover, KCNQ1 variably modulates LQTS2 mutations with distinct underlying pathologies.