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 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 Ca V 1.3, restores neurotransmitter release. We find that chimeric Ca V 1.3s with Ca V 2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release sensitive to Ca V 1 blockers. This dominant targeting function of the Ca V 2.1 C-terminus requires the first 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 and function. We conclude that Ca V intracellular C-termini mediate compartment-specific targeting. [Display omitted] • Ca V 2.1s, but not Ca V 1.3s, are at the active zone and trigger neurotransmitter release • Swapping the Ca V 2.1 C-terminus onto Ca V 1.3 confers active zone targeting to Ca V 1.3 • Ca V 1.3 with the Ca V 2.1 C-terminus mediates release that is L-type blocker sensitive • The first EF hand in the C-terminus is required for Ca V 2.1 active zone targeting Voltage-gated Ca²⁺ channel subtypes are differentially sorted into the soma, dendrites, and axon of a neuron. Chin et al. find that the intracellular C-termini of Ca V 1 and Ca V 2 channels are key determinants for compartment targeting and report an essential trafficking role for the first EF hand of Ca V 2.1. [ABSTRACT FROM AUTHOR]