Abstract
Rationale: L-type Ca2+ (CaV1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of CaV1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances CaV1.2-LQT8 currents and generates lethal arrhythmias are unclear. Objective: To test the hypothesis that the anchoring protein AKAP150 modulates CaV1.2-LQT8 channel gating in ventricular myocytes. Methods and Results: Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that CaV1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca V1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of CaV1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in CaV1.2-LQT8 channels and protects the heart from arrhythmias. Conclusion: We propose that AKAP150-dependent changes in Ca V1.2-LQT8 channel gating may constitute a novel general mechanism for CaV1.2-driven arrhythmias.
Original language | English (US) |
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Pages (from-to) | 255-261 |
Number of pages | 7 |
Journal | Circulation Research |
Volume | 109 |
Issue number | 3 |
DOIs | |
State | Published - Jul 22 2011 |
Externally published | Yes |
Keywords
- arrhythmias
- Ca1.2 channels
- calcium
- EC coupling
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine