The intracellular C-terminus confers compartment-specific targeting of voltage-gated Ca 2+ 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 Ca 2+ channels (Ca V s) to distinct subcellular compartments. In hippocampal neurons, Ca V 2s trigger neurotransmitter release at the presynaptic active zone, and Ca V 1s localize somatodendritically. After knockout of all three Ca V 2s, expression of Ca V 2.1, but not of Ca V 1.3, restores neurotransmitter release. Chimeric Ca V 1.3 channels with Ca V 2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release fully sensitive to blockade of Ca V 1 channels. This dominant targeting function of the Ca V 2.1 C-terminus requires an EF hand in its proximal segment, and replacement of the Ca V 2.1 C-terminus with that of Ca V 1.3 abolishes Ca V 2.1 active zone localization. We conclude that the intracellular C-termini mediate compartment-specific Ca V targeting.