G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain.
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 (CaV1.3) 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 CaV1.3-interacting Shank isoforms that colocalized with PSD-95 and CaV1.3a channels in puncta resembling spines on which glutamatergic corticostriatal synapses are formed. The modulation of CaV1.3 channels by D2 and M1 receptors was disrupted by intracellular dialysis of a peptide designed to compete for the CaV1.3 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 CaV1.3 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.
Olson
Patricia A
PA
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Tkatch
Tatiana
T
Hernandez-Lopez
Salvador
S
Ulrich
Sasha
S
Ilijic
Ema
E
Mugnaini
Enrico
E
Zhang
Hua
H
Bezprozvanny
Ilya
I
Surmeier
D James
DJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D018491:Dopamine Agonists / Q000494:pharmacology; D051528:Guanylate Kinases; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009116:Muscarine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
C425777:10,11-dihydroxy-N-n-propylnorapomorphine; C485995:Cacna1d protein, mouse; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018491:Dopamine Agonists; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D043643:Receptor, Muscarinic M1; D017448:Receptors, Dopamine D2; C492356:Shank3 protein, mouse; C033652:postsynaptic density proteins; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009116:Muscarine; D051528:Guanylate Kinases; D001058:Apomorphine