L-Type Ca 2+ Channel Function During Timothy Syndrome

摘要

Voltage-gated, dihydropyridine-sensitive L-type Ca 2+ channels are multimeric proteins composed of a pore-forming transmembrane α 1 subunit (Ca v1.2) and accessory β, α 2δ, and γ subunits. Ca 2+ entry via Ca v1.2 channels shapes the action potential (AP) of cardiac myocytes and is required for excitation-contraction coupling. Two de novo point mutations of Ca v1.2 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 v1.2 channels bearing TS mutations display slowed inactivation that leads to increased Ca 2+ 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 v1.2-TS channels and facilitates physical interactions among adjacent channels via their C-tails, increasing the activity of adjoining channels and amplifying Ca 2+ influx.