Ca 2+ signaling amplification by oligomerization of L-type Ca v 1.2 channels

• DOI: 10.1073/pnas.1116731109
• Publication Date: 2012-01-18T05:37:35Z
• Authors: Rose E. Dixon; Can Yuan; Edward P. Cheng; Manuel F. Navedo; Luis F. Santana
• Keywords: 0301 basic medicine; 03 medical and health sciences; Biopolymers; Calcium Channels, L-Type; Heart Ventricles; Mutation; Biophysics; Animals; Calcium Signaling; Ion Channel Gating

Ca 2+ influx via L-type Ca v 1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v 1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v 1.2 channels with Ca v 1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v 1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v 1.2-TS increasing the activity of adjoining WT Ca v 1.2 channels. Collectively, these data support the concept that oligomerization of Ca v 1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.