2004, English, Article
Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells
Teng, GuoQi; Zhao, Xiang; Cross, James C; ...
Objective: The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes. Methods and results: Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three I Kr phenotypes were observed: (1) the wildtype-like I Kr showed inward rectification and a positive tail current; (2) the N629D-like I Kr showed outward rectification and an inward tail current; and (3) intermediate I Kr showed a small outward tail current. Action potentials (AP) were paired with the I Kr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the I Kr phenotype. The resting membrane potential of the cells was –61±5 mV ( n = 40) in wildtype, –63±3 mV ( n = 18) in wildtype-like I Kr phenotype, –30±2 mV ( n = 12) in N629D-like and –47±2 mV ( n = 24) in intermediate phenotype ( p <0.00001). Triggered action potential durations (APD) were: 62±12 ms ( n = 6) in wildtype, 65±11 ms ( n = 6) in wildtype-like I Kr phenotypes and 106±10 ms ( n = 6) ( p <0.01) in intermediate I Kr phenotypes. Lowering [K+] o hyperpolarized wildtype cells and cells with a wildtype-like I Kr phenotype, but depolarized those with intermediate phenotype (from –45±1 to –35±0.5 mV ( n = 12), p <0.01). In 6 of 12 cells, with intermediate phenotype, the hypokalemia-induced depolarization resulted in triggered activity. TTX suppressed this triggered activity. Conclusion: Overexpression of N629D in cardiomyocytes derived from stem cells results in phenotypic variability in I Kr , which was the critical determinant of the resting membrane potential, action potential duration and arrhythmogenic response to low [K+] o .
Copyright (C) 2004, European Society of Cardiology
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