Calcium channels work together

eLife 5, e15744 (2016)

Ca_v1.3 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 Ca_v channels. From monitoring Ca²⁺-dependent facilitation (CDF), a regulatory mechanism induced by Ca_v1.3 channel opening, in a human cell line, Moreno et al. found that whereas the short Ca_v1.3 channel splice variant, Ca_v1.3_S, was subject to CDF, the long form, Ca_v1.3_L, was not. By TIRF microscopy, Ca_v1.3_S-expressing cells showed greater numbers of multiquantal Ca²⁺-influx events than Ca_v1.3_L-expressing cells did, suggesting a cooperative gating mechanism whereby multiple Ca_v1.3_S channels are active simultaneously. Super-resolution microscopy followed by step-photobleaching and optogenetic experiments revealed that Ca_v1.3_S 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 Ca_v1.3_S 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.