Association of neuronal calcium channels with modular adaptor proteins

Presynaptic voltage-gated calcium (Ca²⁺) channels mediate Ca²⁺ influx into the presynaptic terminal that triggers synaptic vesicle fusion and neurotransmitter release. The immediate proximity of Ca²⁺ channels to the synaptic vesicle release apparatus is critical for rapid and efficient synaptic transmission. In a series of biochemical experiments, we demonstrate a specific association of the cytosolic carboxyl terminus of the N-type Ca²⁺ channel pore-forming α(1B) subunit with the modular adaptor proteins Mint1 and CASK. The carboxyl termini of α(1B) bind to the first PDZ domain of Mint1 (Mint1-1). The proline-rich region present in the carboxyl termini of α(1B) binds to the SH3 domain of CASK. Mint1-1 is specific for the E/D-X- W-C/S-COOH consensus, which defines a novel class of PDZ domains (class III). The Mint1-1 PDZ domain-binding motif is present only in the 'long' carboxyl- terminal splice variants of N-type (α(1B)) and P/Q-type (α(1A)) Ca²⁺ channels, but not in R-type (α(1E)) or L-type (α(1C)) Ca²⁺ channels. Our results directly link presynaptic Ca²⁺ channels to a macromolecular complex formed by modular adaptor proteins at synaptic junction and advance our understanding of coupling between cell adhesion and synaptic vesicle exocytosis.