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

Abstract

Ca²⁺ influx via L-type Ca_v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca²⁺ 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_v1.2 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 Ca²⁺ influx and excitation-contraction coupling. Light-induced fusion of WT Ca_v1.2 channels with Ca_v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca_v1.2-TS) increased Ca²⁺ currents, diastolic and systolic Ca²⁺ levels, contractility and the frequency of arrhythmogenic Ca²⁺ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca²⁺ signaling resulted from Ca_v1.2-TS increasing the activity of adjoining WT Ca_v1.2 channels. Collectively, these data support the concept that oligomerization of Ca_v1.2 channels via their C termini can result in the amplification of Ca²⁺ influx into excitable cells.