Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels.
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.
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
Rose E
RE
Dixon
Can
C
Yuan
Edward P
EP
Cheng
Manuel F
MF
Navedo
Luis F
LF
Santana
D000818:Animals; D001704:Biopolymers / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D006352:Heart Ventricles / Q000378:metabolism; D015640:Ion Channel Gating; D009154:Mutation
D001704:Biopolymers; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C)