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 Ca channels (Cas) to distinct subcellular compartments. In hippocampal neurons, Ca2s trigger neurotransmitter release at the presynaptic active zone, and Ca1s localize somatodendritically. After knockout of all three Ca2s, expression of Ca2.1, but not Ca1.3, restores neurotransmitter release. We find that chimeric Ca1.3s with Ca2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release sensitive to Ca1 blockers. This dominant targeting function of the Ca2.1 C-terminus requires the first EF hand in its proximal segment, and replacement of the Ca2.1 C-terminus with that of Ca1.3 abolishes Ca2.1 active zone localization and function. We conclude that Ca intracellular C-termini mediate compartment-specific targeting.