Oral Presentation Abstracts Cooperative Gating by Clustered Voltage-gated Cav1.3 Channels Enhances Inward Currents in Neurons the Subprimary Range and Force Generation in the Cat

L-type voltage-gated Cav1.3 (α1D) channels play a critical role in the amplification of synaptic inputs and the generation of persistent activity in motoneurons. As is the case for the other classes of voltage-gated channels, it is widely assumed that individual Cav1.3 channels behave independently with respect to voltage-activation, channel open time, and inactivation. With super-resolution fluorescent imaging, optogenetic, and electrophysiology measurements we have results that -contrary to this long-held view -suggest that Cav1.3 channels form functional homomeres. Our data reveal that a vast majority of Cav1.3 channels associate in clusters of two or more channels that undergo coupled gating through a physical interaction of their carboxyterminus tails. Membrane depolarization induces Cav1.3 carboxy tail-to-carboxy tail interactions, but indirectly, by increasing calcium influx. Calcium binding to calmodulin is necessary for Cav1.3 C-tail oligomerization. We propose that cooperative gating of Cav1.3 channels is a general mechanism for the amplification of calcium currents and facilitation of neuronal discharge.