Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression

Ferzin Sethna, Ming Zhang, Hanoch Kaphzan, Eric Klann, Dawn Autio, Charles L. Cox, Hongbing Wang

Research output: Contribution to journalArticle

Abstract

Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca2+ and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca2+ regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca2+ sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p70-S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca2+/CaM-dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca2+ and protein upregulation and regulating mGluR1/5-mediated synaptic modification.

Original languageEnglish (US)
JournalJournal of Neuroscience Research
DOIs
StateAccepted/In press - 2016

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Metabotropic Glutamate Receptors
Calmodulin
Signal Transduction
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Calcium-Calmodulin-Dependent Protein Kinases
Up-Regulation
Metabotropic Glutamate 5 Receptor
Ribosomal Protein S6 Kinases
70-kDa Ribosomal Protein S6 Kinases
Neuronal Plasticity
metabotropic glutamate receptor type 1
Protein Biosynthesis
Proteins
Pharmacology
Neurons

Keywords

  • AB_2265913
  • AB_331647
  • AB_823494
  • AB_823592
  • AB_887694
  • Arc
  • Calmodulin
  • ERK1/2
  • MGluR1/5
  • Signal transduction
  • Synaptic depression

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression. / Sethna, Ferzin; Zhang, Ming; Kaphzan, Hanoch; Klann, Eric; Autio, Dawn; Cox, Charles L.; Wang, Hongbing.

In: Journal of Neuroscience Research, 2016.

Research output: Contribution to journalArticle

Sethna, Ferzin ; Zhang, Ming ; Kaphzan, Hanoch ; Klann, Eric ; Autio, Dawn ; Cox, Charles L. ; Wang, Hongbing. / Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression. In: Journal of Neuroscience Research. 2016.
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AU - Sethna, Ferzin

AU - Zhang, Ming

AU - Kaphzan, Hanoch

AU - Klann, Eric

AU - Autio, Dawn

AU - Cox, Charles L.

AU - Wang, Hongbing

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AB - Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca2+ and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca2+ regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca2+ sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p70-S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca2+/CaM-dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca2+ and protein upregulation and regulating mGluR1/5-mediated synaptic modification.

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