The intracellular C-terminus confers compartment-specific targeting of voltage-gated calcium channels

To achieve the functional polarization that underlies brain computation, neurons sort protein material into distinct compartments. Ion channel composition, for example, differs between axons and dendrites, but the molecular determinants for their polarized trafficking remain obscure. Here, we identify mechanisms that target voltage-gated Ca²⁺ channels (Ca_Vs) to distinct subcellular compartments. In hippocampal neurons, Ca_V2s trigger neurotransmitter release at the presynaptic active zone, and Ca_V1s localize somatodendritically. After knockout of all three Ca_V2s, expression of Ca_V2.1, but not Ca_V1.3, restores neurotransmitter release. We find that chimeric Ca_V1.3s with Ca_V2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release sensitive to Ca_V1 blockers. This dominant targeting function of the Ca_V2.1 C-terminus requires the first EF hand in its proximal segment, and replacement of the Ca_V2.1 C-terminus with that of Ca_V1.3 abolishes Ca_V2.1 active zone localization and function. We conclude that Ca_V intracellular C-termini mediate compartment-specific targeting.