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)
Pages (from-to)401-408
Number of pages8
JournalJournal of neuroscience research
Volume94
Issue number5
DOIs
StatePublished - May 1 2016

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

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