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.