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

ABSTRACT:

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 for

SUBMITTER: Cheng EP 

PROVIDER: S-EPMC3151468 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature