The intracellular C-terminus confers compartment-specific targeting of voltage-gated Ca2+ 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 the mechanisms that target voltage-gated Ca2+ channels (CaVs) to distinct subcellular compartments. In hippocampal neurons, CaV2s trigger neurotransmitter release at the presynaptic active zone, and CaV1s localize somatodendritically. After knockout of all three CaV2s, expression of CaV2.1, but not of CaV1.3, restores neurotransmitter release. Chimeric CaV1.3 channels with CaV2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release fully sensitive to blockade of CaV1 channels. This dominant targeting function of the CaV2.1 C-terminus requires an EF hand in its proximal segment, and replacement of the CaV2.1 C-terminus with that of CaV1.3 abolishes CaV2.1 active zone localization. We conclude that the intracellular C-termini mediate compartment-specific CaV targeting.