G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain

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

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)1050-1062
Number of pages13
JournalJournal of Neuroscience
Volume25
Issue number5
DOIs
StatePublished - Feb 2 2005

Fingerprint

Corpus Striatum
G-Protein-Coupled Receptors
Neurons
PDZ Domains
Post-Synaptic Density
Synapses
Muscarinic M1 Receptors
Peptides
Neuronal Plasticity
Herpes Zoster
Dialysis
Protein Isoforms
Spine
Gene Expression
Proteins

Keywords

  • Acetylcholine
  • Basal ganglia
  • Ca1.2
  • Ca1.3
  • Dopamine
  • L-type channels
  • Neuromodulation
  • Patch clamp
  • PDZ domain
  • PSD-95
  • State transitions

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Olson, P. A., Tkatch, T., Hernandez-Lopez, S., Ulrich, S., Ilijic, E., Mugnaini, E., ... Surmeier, D. J. (2005). G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain. Journal of Neuroscience, 25(5), 1050-1062. https://doi.org/10.1523/JNEUROSCI.3327-04.2005

G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain. / Olson, Patricia A.; Tkatch, Tatiana; Hernandez-Lopez, Salvador; Ulrich, Sasha; Ilijic, Ema; Mugnaini, Enrico; Zhang, Hua; Bezprozvanny, Ilya; Surmeier, D. James.

In: Journal of Neuroscience, Vol. 25, No. 5, 02.02.2005, p. 1050-1062.

Research output: Contribution to journalArticle

Olson, Patricia A. ; Tkatch, Tatiana ; Hernandez-Lopez, Salvador ; Ulrich, Sasha ; Ilijic, Ema ; Mugnaini, Enrico ; Zhang, Hua ; Bezprozvanny, Ilya ; Surmeier, D. James. / G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 5. pp. 1050-1062.
@article{e19f55a22041436ebcd6a227b3ac625a,
title = "G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain",
abstract = "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 Ca 2+ 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.",
keywords = "Acetylcholine, Basal ganglia, Ca1.2, Ca1.3, Dopamine, L-type channels, Neuromodulation, Patch clamp, PDZ domain, PSD-95, State transitions",
author = "Olson, {Patricia A.} and Tatiana Tkatch and Salvador Hernandez-Lopez and Sasha Ulrich and Ema Ilijic and Enrico Mugnaini and Hua Zhang and Ilya Bezprozvanny and Surmeier, {D. James}",
year = "2005",
month = "2",
day = "2",
doi = "10.1523/JNEUROSCI.3327-04.2005",
language = "English (US)",
volume = "25",
pages = "1050--1062",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "5",

}

TY - JOUR

T1 - G-protein-coupled receptor modulation of striatal Cav1.3 L-type Ca2+ channels is dependent on a shank-binding domain

AU - Olson, Patricia A.

AU - Tkatch, Tatiana

AU - Hernandez-Lopez, Salvador

AU - Ulrich, Sasha

AU - Ilijic, Ema

AU - Mugnaini, Enrico

AU - Zhang, Hua

AU - Bezprozvanny, Ilya

AU - Surmeier, D. James

PY - 2005/2/2

Y1 - 2005/2/2

N2 - 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 Ca 2+ 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.

AB - 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 Ca 2+ 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.

KW - Acetylcholine

KW - Basal ganglia

KW - Ca1.2

KW - Ca1.3

KW - Dopamine

KW - L-type channels

KW - Neuromodulation

KW - Patch clamp

KW - PDZ domain

KW - PSD-95

KW - State transitions

UR - http://www.scopus.com/inward/record.url?scp=13944262462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13944262462&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3327-04.2005

DO - 10.1523/JNEUROSCI.3327-04.2005

M3 - Article

C2 - 15689540

AN - SCOPUS:13944262462

VL - 25

SP - 1050

EP - 1062

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 5

ER -