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The Journal of Neuroscience, February 2, 2005, 25(5):1037-1049; doi:10.1523/JNEUROSCI.4554-04.2005

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Cellular/Molecular
Association of Ca_V1.3 L-Type Calcium Channels with Shank

Hua Zhang,¹ Anton Maximov,¹ Yu Fu,¹ Fang Xu,¹ Tie-Shan Tang,¹ Tatiana Tkatch,² D. James Surmeier,² and Ilya Bezprozvanny¹

¹Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and ²Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Neurons express multiple types of voltage-gated calcium (Ca²⁺) channels. Two subtypes of neuronal L-type Ca²⁺ channels are encoded by Ca_V1.2 and Ca_V1.3 pore-forming subunits. Both Ca_V1.2 and Ca_V1.3 subunits contain class I PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-binding consensus at their C termini. In yeast two-hybrid screen of rat brain cDNA library with the C-terminal bait of Ca_V1.3a (long C-terminal splice variant) L-type Ca²⁺ channel subunit, we isolated multiple clones of postsynaptic adaptor protein Shank. We demonstrated a specific association of Ca_V1.3a C termini, but not of Ca_V1.2 C termini, with Shank PDZ domain in vitro. We further demonstrated that the proline-rich region present in C termini of Ca_V1.3a subunit binds to Shank Src homology 3 domain. We established that Ca_V1.3a and Shank localized to postsynaptic locations in cultured rat hippocampal neurons. By expressing epitope-tagged recombinant Ca_V1.3 subunits in rat hippocampal neuronal cultures, we demonstrated that the presence of Shank-binding motifs in Ca_V1.3a sequence is both necessary and sufficient for synaptic clustering of Ca_V1.3 L-type Ca²⁺ channels. In experiments with dominant-negative peptides and dihydropyridine-resistant Ca_V1.3a mutants, we demonstrated an importance of Shank-binding motif in Ca_V1.3a sequence for phosphorylated cAMP response element-binding protein (pCREB) signaling in cultured hippocampal neurons. Our results directly link Ca_V1.3 neuronal L-type Ca²⁺ channels to macromolecular signaling complex formed by Shank and other modular adaptor proteins at postsynaptic density and provide novel information about the role played by Ca_V1.3 L-type Ca²⁺ channels in pCREB signaling.

Key words: calcium channels; PDZ domains; protein targeting; postsynaptic density; CREB; synapse; synaptic plasticity

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Received Aug 9, 2004; revised December 10, 2004; accepted December 14, 2004.

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