alternative splicing of the cardiac sodium channel creates multiple variants of mutant t1620k channels可变剪接的心脏钠通道创建多个变异的突变t1620k通道.pdfVIP

Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels Stefan Walzik, Annett Schroeter, Klaus Benndorf, Thomas Zimmer* Institute of Physiology II, University Hospital Jena, Friedrich Schiller University, Jena, Germany Abstract Alternative splicing creates several Na 1.5 transcripts in the mammalian myocardium and in various other tissues including v brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Nav 1.5 splice variants have been discovered. Four of them, namely Na 1.5a, Na 1.5c, Na 1.5d, and Na 1.5e, generate functional channels in v v v v heterologous expression systems. The significance of alternatively spliced transcripts for cardiac excitation, in particular their role in SCN5A channelopathies, is less well understood. In the present study, we systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Nav 1.5 splice variants in HEK293 cells. This mutation has been previously associated with two distinct cardiac excitation disorders: with long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, we noticed similar channel defects in the background of hNa 1.5, hNa 1.5a, and hNa 1.5c. In contrast, the v v v hNav 1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, wh