Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants

Zheng, Yueming; Zhu, Xuejing; Zhou, Pingzheng; Lan, Xi; Xu, Haiyan; Li, Min; Gao, Zhaobing

Mutations in KCNQ1 have been found to cause LQTs [1, 19] . The common phenotype of these mutants is reduction of IKs current, which are commonly thought to be mediated by the KCNQ1/KCNE1 complex [2, 3] , as a result of decrease in either channel activity or trafficking efficiency. HCP has exhibited potent effects on both the homomeric KCNQ1 and the KCNQ1/ KCNE1 complex; we thus hypothesize its ability to rescue the function reduction of these mutants. We selected and expressed four mutants, R190Q, T587M, R243C and R539W, which are located in different regions of KCNQ1. Among these mutants, R243C and R539W exhibited low but consistent currents, while the others did not exhibit detectable currents in CHO cells. R243 is located near the C-terminal end of S4 transmembrane domain, while R539W is located at the C-terminal tail [20, 21] . Mutations R243C and R539W were thought to impair activation gating or to reduce PIP2 binding affinity, respectively. In the current study, both homomeric mutant channels were significantly potentiated by 10 mM HCP. The potentiation on R243C and R539W were comparable with that on KCNQ1 wild type ( Fig. 6 and Table 2 ). We next tested whether HCP was effective on the mutant/ KCNE1 and found that both complexes were also sensitive to 10 mM HCP. The outward currents of R243C/KCNE1 and R539W/KCNE1 were potentiated by 1.4460.33 (n = 5) and 2.9160.89 (n = 5) fold, respectively. The effects of HCP on voltage-dependent activation of the mutant channels were also examined and the results are shown in Table 2 . Besides R243C/ KCNE1, the G-V curves of all tested mutant channels were leftshifted by 10 mM HCP.