L-type calcium channels are ubiquitously expressed in excitable cells. They are engaged in a wide range of physiological processes including excitation-contraction coupling in muscle, hormone secretion, gene transcription, and repetitive neural discharge.

As is the case for all voltage-gated channels, it is widely assumed that individual L-type calcium channels behave independently with respect to voltage-activation, open probability, and facilitation. In this talk, I will describe the results of super-resolution fluorescent imaging, optogenetic measurements, and electrophysiological measurements that refute this long-held view.

We have found that both the Cav1.2 channel that is expressed predominantly in muscle cells and the Cav1.3 channel that is expressed preferentially in neurons associate in functional clusters of two or more channels that open cooperatively, facilitating Ca2+ influx. Both channel types are coupled via C-terminus-to-C-terminus interactions that require binding of the incoming Ca2+ to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels.

Physically-coupled L-type channels facilitate Ca2+ currents as a consequence of their higher open probabilities, leading to the highly reliable heartbeat observed in cardiac tissue and increased firing rates in neurons.

We propose that cooperative gating of L-type calcium channels represents a novel mechanism for the regulation of Ca2+ signaling and electrical activity.