eLife 5, e15744 (2016)

Cav1.3 channels are voltage-gated channels that allow the passage of Ca2+ ions into cells, including hippocampal neurons, and recent studies have raised the possibility that Ca2+ influx is facilitated by interactions between neighboring Cav channels. From monitoring Ca2+-dependent facilitation (CDF), a regulatory mechanism induced by Cav1.3 channel opening, in a human cell line, Moreno et al. found that whereas the short Cav1.3 channel splice variant, Cav1.3S, was subject to CDF, the long form, Cav1.3L, was not. By TIRF microscopy, Cav1.3S-expressing cells showed greater numbers of multiquantal Ca2+-influx events than Cav1.3L-expressing cells did, suggesting a cooperative gating mechanism whereby multiple Cav1.3S channels are active simultaneously. Super-resolution microscopy followed by step-photobleaching and optogenetic experiments revealed that Cav1.3S clusters in hippocampal neurons, with a mean of eight channels per cluster, and the channels physically interact within the clusters. Ca2+ binding to calmodulin (CaM) was required for the channel coupling, which increased the firing rate in hippocampal neurons. These results point to a mechanism where Cav1.3S undergoes cooperative gating through functional coupling supported by CaM association with the channels, ultimately leading to regulation of neuronal excitability through amplification of Ca2+ signals.