NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Sudar Alagarsamy, Julie Saugstad, Lee Warren, Isabelle M. Mansuy, Robert W. Gereau IV, P. Jeffrey Conn

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Previous reports have shown that activation of N-methyl-d-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

Original languageEnglish (US)
Pages (from-to)135-145
Number of pages11
JournalNeuropharmacology
Volume49
Issue numberSUPPL.
DOIs
StatePublished - 2005
Externally publishedYes

Fingerprint

Calcineurin
Aspartic Acid
Phosphoprotein Phosphatases
Molecular Biology
Metabotropic Glutamate 5 Receptor
Metabotropic Glutamate Receptors
Immunoprecipitation
Calcium
aspartic acid receptor
Proteins

Keywords

  • Glutamate
  • LTD
  • LTP
  • Metabotropic
  • PKC
  • Plasticity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. / Alagarsamy, Sudar; Saugstad, Julie; Warren, Lee; Mansuy, Isabelle M.; Gereau IV, Robert W.; Conn, P. Jeffrey.

In: Neuropharmacology, Vol. 49, No. SUPPL., 2005, p. 135-145.

Research output: Contribution to journalArticle

Alagarsamy, Sudar ; Saugstad, Julie ; Warren, Lee ; Mansuy, Isabelle M. ; Gereau IV, Robert W. ; Conn, P. Jeffrey. / NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. In: Neuropharmacology. 2005 ; Vol. 49, No. SUPPL. pp. 135-145.
@article{03ff11611ba0477691be9a71008cbdd9,
title = "NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin",
abstract = "Previous reports have shown that activation of N-methyl-d-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.",
keywords = "Glutamate, LTD, LTP, Metabotropic, PKC, Plasticity",
author = "Sudar Alagarsamy and Julie Saugstad and Lee Warren and Mansuy, {Isabelle M.} and {Gereau IV}, {Robert W.} and Conn, {P. Jeffrey}",
year = "2005",
doi = "10.1016/j.neuropharm.2005.05.005",
language = "English (US)",
volume = "49",
pages = "135--145",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "SUPPL.",

}

TY - JOUR

T1 - NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

AU - Alagarsamy, Sudar

AU - Saugstad, Julie

AU - Warren, Lee

AU - Mansuy, Isabelle M.

AU - Gereau IV, Robert W.

AU - Conn, P. Jeffrey

PY - 2005

Y1 - 2005

N2 - Previous reports have shown that activation of N-methyl-d-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

AB - Previous reports have shown that activation of N-methyl-d-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

KW - Glutamate

KW - LTD

KW - LTP

KW - Metabotropic

KW - PKC

KW - Plasticity

UR - http://www.scopus.com/inward/record.url?scp=23644445510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23644445510&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2005.05.005

DO - 10.1016/j.neuropharm.2005.05.005

M3 - Article

VL - 49

SP - 135

EP - 145

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - SUPPL.

ER -