Abstract
The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the Kv7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid Kv7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of Kv7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, Kv7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by Kv7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast Kv7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.
Highlights
Emotional and physical stress reactions involve hypothalamic structures leading to an activation of the sympathetic nervous system (SNS)
Mechanisms underlying the putative short-term regulation of Kv7.1/KCNE1 are essentially unexplored in human cardiomyocytes, though, largely because these cells are barely accessible for experimental purposes
Several congenital diseases including LQT1 are associated with protein misfolding, result in impaired intrinsic protein functionality or lead to incorrect protein localization due to trafficking defects
Summary
Emotional and physical stress reactions involve hypothalamic structures leading to an activation of the sympathetic nervous system (SNS). The HPA axis controls stress reactions and regulates many body processes including cardiac function. Activation of β1-receptors during FFR increases the heart rate (chronotropy) through pacemaker cells and stimulates force development (inotropy) (Bers, 2002). Both effects require a physiological adaptation of the working myocardium supposedly again through a modulation of Kv7.1/KCNE1 function, which would have to occur very rapidly during FFR initiation. Based on in-vitro studies, it has been shown in this context that β-adrenergic stimulation impacts on Kv7.1/KCNE1 channel kinetics (Marx et al, 2002). These positive effects, are not extensive enough to explain the full extent of Kv7.1/KCNE1 stimulation by β-adrenergic activation (Nicolas et al, 2008)
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