Restoration of normal L-type Ca2+ channel function during timothy syndrome by ablation of an anchoring protein

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. © 2011 American Heart Association, Inc.