L-Type Ca2+ Channel Function During Timothy Syndrome

Voltage-gated, dihydropyridine-sensitive L-type Ca2+ channels are multimeric proteins composed of a pore-forming transmembrane alpha(1) subunit (Ca(v)1.2) and accessory beta, alpha(2)beta, and gamma subunits. Ca2+ entry via Ca(v)1.2 channels shapes the action potential (AP) of cardiac myocytes and is required for excitation-contraction coupling. Two de novo point mutations of Ca(v)1.2 glycine residues, G406R and G402S, cause a rare multisystem disorder called Timothy syndrome (TS). Here, we discuss recent work on the mechanisms by which Ca(v)1.2 channels bearing TS mutations display slowed inactivation that leads to increased Ca2+ influx, prolonging the cardiac AP and promoting lethal arrhythmias. Based on these studies, we propose a model in which the scaffolding protein AKAP79/150 stabilizes the open conformation of Ca(v)1.2-TS channels and facilitates physical interactions among adjacent channels via their C-tails, increasing the activity of adjoining channels and amplifying Ca2+ influx. (Trends Cardiovasc Med 2012;22:72-76) (c) 2012 Elsevier Inc. All rights reserved.