Graded Ca(2+)/calmodulin-dependent coupling of voltage-gated Ca(V)1.2 channels

In the heart, reliable activation of Ca(2+) release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple Ca(V)1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that Ca(V)1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This ‘functional coupling’ facilitates Ca(2+) influx by increasing activation of adjoined channels and occurs through C-terminal-to-C-terminal interactions. These interactions are initiated by binding of incoming Ca(2+) to calmodulin (CaM) and proceed through Ca(2+)/CaM binding to the Ca(V)1.2 pre-IQ domain. Coupling fades as [Ca(2+)](i) decreases, but persists longer than the current that evoked it, providing evidence for ‘molecular memory’. Our findings suggest a model for Ca(V)1.2 channel gating and Ca(2+)-influx amplification that unifies diverse observations about Ca(2+) signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently. DOI: http://dx.doi.org/10.7554/eLife.05608.001