Impaired IKs channel activation by Ca2+-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1
| Autor: | Xiaorong Xu Parks, Coeli M. Lopes, Wojciech Zareba, Arthur J. Moss, Jin O-Uchi, Elsa Ronzier, Martin H. Ruwald, John Rice |
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| Rok vydání: | 2015 |
| Předmět: |
Cell physiology
medicine.medical_specialty Emotions Action Potentials Adrenergic Article Arousal Risk Factors Internal medicine Receptors Adrenergic beta medicine Humans KvLQT1 Phosphorylation Receptor Molecular Biology Protein Kinase C Protein kinase C Proportional Hazards Models biology business.industry Cardiac arrhythmia Receptors Adrenergic alpha Cyclic AMP-Dependent Protein Kinases Potassium channel Isoenzymes Long QT Syndrome HEK293 Cells Endocrinology Potassium Channels Voltage-Gated KCNQ1 Potassium Channel Mutation biology.protein Calcium Mutant Proteins Cardiology and Cardiovascular Medicine business Ion Channel Gating Signal Transduction |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 79:203-211 |
| ISSN: | 0022-2828 |
| Popis: | 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 s-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. |
| Databáze: | OpenAIRE |
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