Non-Genomic Regulation of Cardiac Ion Channels by Sex Hormones

In addition to their canonical genomic action, sex hormones exhibit acute actions, which are designated as the non-genomic action. Non-genomic action takes only several seconds to minutes and takes place in a membrane-delimited signal pathway. We recently find in cardiac myocytes that testosterone, progesterone, and a high-concentration of 17β- estradiol acutely shorten cardiac repolarization time by regulating L-type Ca2+ current (ICa,L) and slowly-activating delayed rectifier K+ current (IKs). The regulation of ICa,L and IKs occurs via the non-genomic pathway involving sequential activation of c-Src, PI3-kinase, Akt, and eNOS and resultant release of nitric oxide (NO), which occur in the caveolae/ lipid raft domain. NO inhibits ICa,L, only when ICa,L had been activated by sympathetic nervous system stimulation via antagonistic action between cAMP/protein kinase A and cGMP/protein kinase G/phosphodiesterase signals. NO likely to enhance IKs in the basal condition via the protein s-nitrosylation mechanism. The non-genomic regulation by sex hormones is a novel regulatory mechanism of cardiac ion channels, and may be involved, in part, in the development of gender difference and dynamic fluctuation of QTc interval and arrhythmic risk during the menstrual cycle.