Impaired IKs channel activation by Ca(2+)-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1.

ABSTRACT: The most common inherited cardiac arrhythmia, LQT1, is due to IKs potassium channel mutations and is linked to high risk of adrenergic-triggered cardiac events. We recently showed that although exercise-triggered events are very well treated by ß-blockers for these patients, acute arousal-triggered event rate were not significantly reduced after beta-blocker treatment, suggesting that the mechanisms underlying arousal-triggered arrhythmias may be different from those during exercise. IKs is strongly regulated by ?-adrenergic receptor (?-AR) signaling, but little is known about the role of ?1-AR-mediated regulation.Here we show, using a combination of cellular electrophysiology and computational modeling, that IKs phosphorylation and ?1-AR regulation via activation of calcium-dependent PKC isoforms (cPKC) may be a key mechanism to control channel voltage-dependent activation and consequently action potential duration (APD) in response to adrenergic-stimulus. We show that simulated mutation-specific combined adrenergic effects (?+?) on APD were strongly correlated to acute stress-triggered cardiac event rate for patients while ?-AR effects alone were not.We were able to show that calcium-dependent PKC signaling is key to normal QT shortening during acute arousal and when impaired, correlates with increased rate of sudden arousal-triggered cardiac events. Our study suggests that the acute ?1-AR-cPKC regulation of IKs is important for QT shortening in "fight-or-flight" response and is linked to decreased risk of sudden emotion/arousal-triggered cardiac events in LQT1 patients.

SUBMITTER: O-Uchi J 

PROVIDER: S-EPMC4302024 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature