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The Journal of Neuroscience, August 15, 2002, 22(16):6939-6952

Synaptic Targeting of N-Type Calcium Channels in Hippocampal Neurons

Anton Maximov and Ilya Bezprozvanny

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

N-type calcium (Ca²⁺) channels play a critical role in synaptic function, but the mechanisms responsible for their targeting in neurons are poorly understood. N-type channels are formed by an _1B (Ca_V2.2) pore-forming subunit associated with  and 2 auxiliary subunits. By expressing epitope-tagged recombinant _1B subunits in rat hippocampal neuronal cultures, we demonstrate here that synaptic targeting of N-type channels depends on neuronal contacts and synapse formation. We also establish that the C-terminal 163 aa (2177-2339) of the _1B-1 (Ca_V2.2a) splice variant contain sequences that are both necessary and sufficient for synaptic targeting. By site-directed mutagenesis, we demonstrate that postsynaptic density-95/discs large/zona occludens-1 and Src homology 3 domain-binding motifs located within this region of the _1B subunit (Maximov et al., 1999) act as synergistic synaptic targeting signals. We also show that the recombinant modular adaptor proteins Mint1 and CASK colocalize with N-type channels in synapses. We found that the _1B-2 (Ca_V2.2b) splice variant is restricted to soma and dendrites and postulated that somatodendritic and axonal/presynaptic isoforms of N-type channels are generated via alternative splicing of _1B C termini. These data lead us to propose that during synaptogenesis, the _1B-1 (Ca_V2.2a) splice variant of the N-type Ca²⁺ channel pore-forming subunit is recruited to presynaptic locations by means of interactions with modular adaptor proteins Mint1 and CASK. Our results provide a novel insight into the molecular mechanisms responsible for targeting of Ca²⁺ channels and other synaptic proteins in neurons.

Key words: calcium channels; polarized cells; PDZ domains; protein targeting; axons; synapse

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166939-14$05.00/0

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