CAST/ELKS Proteins Control Voltage-Gated Ca(2+) Channel Density and Synaptic Release Probability at a Mammalian Central Synapse

In the presynaptic terminal, the magnitude and location of Ca(2+) entry through voltage-gated Ca(2+) channels (VGCCs) regulate the efficacy of neurotransmitter release. However, how presynaptic active zone proteins control mammalian VGCC levels and organization is unclear. To address this, we deleted the CAST/ELKS protein family at the calyx of Held, a Ca(V)2.1 channel-exclusive presynaptic terminal. We found that loss of CAST/ELKS reduces the Ca(V)2.1 current density with concomitant reductions in Ca(V)2.1 channel numbers and clusters. Surprisingly, deletion of CAST/ELKS increases release probability while decreasing the readily releasable pool, with no change in active zone ultrastructure. In addition, Ca(2+) channel coupling is unchanged, but spontaneous release rates are elevated. Thus, our data identify distinct roles for CAST/ELKS as positive regulators of Ca(V)2.1 channel density and suggest that they regulate release probability through a post-priming step that controls synaptic vesicle fusogenicity.