mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C

Vytenis A. Skeberdis, Jian Yu Lan, Thoralf Opitz, Xin Zheng, Michael V.L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticle

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Abstract

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1α. The mGluR1 agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1α-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor thapsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated by the broad spectrum kinase inhibitor staurosporine. ACPD produced no further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with a role for cytoskeletal protein(s) in the signaling pathway. As Group I mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.

Original languageEnglish (US)
Pages (from-to)856-865
Number of pages10
JournalNeuropharmacology
Volume40
Issue number7
DOIs
StatePublished - Jun 18 2001

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Keywords

  • (1S,3R)-ACPD
  • Metabotropic glutamate receptors
  • N-Methyl-D-aspartate receptors
  • Phospholipase C
  • Protein kinase C
  • Xenopus oocytes

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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