Impaired IKs channel activation by Ca2+-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1

Jin O-Uchi, J. Jeremy Rice, Martin H. Ruwald, Xiaorong Xu Parks, Elsa Ronzier, Arthur J. Moss, Wojciech Zareba, Coeli M. Lopes

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 β-adrenergic receptor (β-AR) signaling, but little is known about the role of α1-AR-mediated regulation. Methods and results: Here we show, using a combination of cellular electrophysiology and computational modeling, that IKs phosphorylation and α1-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 (β+α) on APD were strongly correlated to acute stress-triggered cardiac event rate for patients while β-AR effects alone were not. Conclusion: 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 α1-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.

Original languageEnglish (US)
Pages (from-to)203-211
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume79
DOIs
StatePublished - Feb 1 2015

Keywords

  • Arrhythmias
  • K
  • KCNE1
  • KvLQT1
  • LQT
  • MinK

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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