title: Impaired IKs channel activation by Ca(2+)-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: O-Uchi
authors.affiliation: Functional Genomics and Systems Biology Group, IBM T.J. Watson Research Center, New York, USA.
authors.forename: J Jeremy
authors.initials: JJ
authors.lastname: Rice
authors.affiliation: Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Ruwald
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Xiaorong Xu
authors.initials: XX
authors.lastname: Parks
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Ronzier
authors.affiliation: Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.affiliation: Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA. Electronic address: coeli_lopes@urmc.rochester.edu.
authors.forename: Coeli M
authors.initials: CM
authors.lastname: Lopes
mesh_terms: D000200:Action Potentials; D001143:Arousal; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004644:Emotions; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D007527:Isoenzymes / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D016016:Proportional Hazards Models; D011493:Protein Kinase C / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D007527:Isoenzymes; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D050505:Mutant Proteins; D024642:Potassium Channels, Voltage-Gated; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium
keywords: Arrhythmias; K(+); KCNE1; KvLQT1; LQT; MinK