Ca(2+) entry into neurons is facilitated by cooperative gating of clustered Ca(V)1.3 channels

Ca(V)1.3 channels regulate excitability in many neurons. As is the case for all voltage-gated channels, it is widely assumed that individual Ca(V)1.3 channels behave independently with respect to voltage-activation, open probability, and facilitation. Here, we report the results of super-resolution imaging, optogenetic, and electrophysiological measurements that refute this long-held view. We found that the short channel isoform (Ca(V)1.3(S)), but not the long (Ca(V)1.3(L)), associates in functional clusters of two or more channels that open cooperatively, facilitating Ca(2+) influx. Ca(V)1.3(S) channels are coupled via a C-terminus-to-C-terminus interaction that requires binding of the incoming Ca(2+) to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels. Physically-coupled channels facilitate Ca(2+) currents as a consequence of their higher open probabilities, leading to increased firing rates in rat hippocampal neurons. We propose that cooperative gating of Ca(V)1.3(S) channels represents a mechanism for the regulation of Ca(2+) signaling and electrical activity. DOI: http://dx.doi.org/10.7554/eLife.15744.001