Key result
Ablation of the anchoring protein AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias in Timothy syndrome models.
Why the study?
Does ablation of AKAP150 restore normal Ca(V)1.2 channel gating and prevent arrhythmias in models of Timothy syndrome (LQT8)?
Does ablation of AKAP150 restore normal Ca(V)1.2 channel gating and prevent arrhythmias in models of Timothy syndrome (LQT8)?
Ablation of AKAP150 restores normal calcium channel gating and prevents arrhythmias in Timothy syndrome models, highlighting a novel mechanism for Ca(V)1.2-driven arrhythmias.
AKAP150 ablation merits further investigation as an antiarrhythmic strategy in Timothy syndrome; leaves open clinical translation from animal models.
RATIONALE: L-type Ca(2+) (Ca(V)1.2) 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 Ca(V)1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca(V)1.2-LQT8 currents and generates lethal arrhythmias are unclear. OBJECTIVE: To test the hypothesis that the anchoring protein AKAP150 modulates Ca(V)1.2-LQT8 channel gating in ventricular myocytes. METHODS AND RESULTS: Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca(V)1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca(V)1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca(V)1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias. CONCLUSION: We propose that AKAP150-dependent changes in Ca(V)1.2-LQT8 channel gating may constitute a novel general mechanism for Ca(V)1.2-driven arrhythmias.
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Cheng et al. (2011) studied Timothy syndrome (long QT syndrome 8). Ablation of AKAP150 was evaluated on Ca(V)1.2-LQT8 channel gating and arrhythmias. Ablation of the anchoring protein AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias in Timothy syndrome models.
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