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The Journal of Neuroscience, February 2, 2005, 25(5):1050-1062; doi:10.1523/JNEUROSCI.3327-04.2005

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Cellular/Molecular
G-Protein-Coupled Receptor Modulation of Striatal Ca_V1.3 L-Type Ca²⁺ Channels Is Dependent on a Shank-Binding Domain

Patricia A. Olson,¹ Tatiana Tkatch,¹ Salvador Hernandez-Lopez,¹ Sasha Ulrich,¹ Ema Ilijic,³ Enrico Mugnaini,^2,3 Hua Zhang,⁴ Ilya Bezprozvanny,⁴ and D. James Surmeier^1,3

Departments of ¹Physiology and ²Cell and Molecular Biology, and ³Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and ⁴Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Voltage-gated L-type Ca²⁺ channels are key determinants of synaptic integration and plasticity, dendritic electrogenesis, and activity-dependent gene expression in neurons. Fulfilling these functions requires appropriate channel gating, perisynaptic targeting, and linkage to intracellular signaling cascades controlled by G-protein-coupled receptors (GPCRs). Surprisingly, little is known about how these requirements are met in neurons. The studies described here shed new light on how this is accomplished. We show that D₂ dopaminergic and M₁ muscarinic receptors selectively modulate a biophysically distinctive subtype of L-type Ca²⁺ channels (Ca_V1.3) in striatal medium spiny neurons. The splice variant of these channels expressed in medium spiny neurons contains cytoplasmic Src homology 3 and PDZ (postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1) domains that bind the synaptic scaffolding protein Shank. Medium spiny neurons coexpressed Ca_V1.3-interacting Shank isoforms that colocalized with PSD-95 and Ca_V1.3a channels in puncta resembling spines on which glutamatergic corticostriatal synapses are formed. The modulation of Ca_V1.3 channels by D₂ and M₁ receptors was disrupted by intracellular dialysis of a peptide designed to compete for the Ca_V1.3 PDZ domain but not with one targeting a related PDZ domain. The modulation also was disrupted by application of peptides targeting the Shank interaction with Homer. Upstate transitions in medium spiny neurons driven by activation of glutamatergic receptors were suppressed by genetic deletion of Ca_V1.3 channels or by activation of D₂ dopaminergic receptors. Together, these results suggest that Shank promotes the assembly of a signaling complex at corticostriatal synapses that enables key GPCRs to regulate L-type Ca²⁺ channels and the integration of glutamatergic synaptic events.

Key words: L-type channels; Ca_V1.2; Ca_V1.3; patch clamp; neuromodulation; PDZ domain; state transitions; basal ganglia; dopamine; acetylcholine; PSD-95

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Received Aug 13, 2004; revised November 16, 2004; accepted December 6, 2004.

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