RGS4 inhibits signaling by group I metabotropic glutamate receptors

Julie A. Saugstad, Michael J. Marino, Julie A. Folk, John R. Hepler, P. Jeffrey Conn

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Metabotropic glutamate receptors (mGluRs) couple to heterotrimeric G- proteins and regulate cell excitability and synaptic transmission in the CNS. Considerable effort has been focused on understanding the cellular and biochemical mechanisms that underlie regulation of signaling by G-proteins and their linked receptors, including the mGluRs. Recent findings demonstrate that regulators of G-protein signaling (RGS) proteins act as effector antagonists and GTPase-activating proteins for G(α) subunits to inhibit cellular responses by G-protein-coupled receptors. RGS4 blocks G(q) activation of phospholipase Cβ and is expressed broadly in rat brain. The group I mGluRs (mGluRs 1 and 5) couple to G(q) pathways to regulate several effectors in the CNS. We examined the capacity of RGS4 to regulate group I mGluR responses. In Xenopus oocytes, purified RGS4 virtually abolishes the mGluR1a- and mGluR5a-mediated but not the inositol trisphosphate-mediated activation of a calcium-dependent chloride current. Additionally, RGS4 markedly attenuates the mGluR5-mediated inhibition of potassium currents in hippocampal CA1 neurons. This inhibition is dose-dependent and occurs at concentrations that are virtually identical to those required for inhibition of phospholipase C activity in NG108-15 membranes and reconstituted systems using purified proteins. These findings demonstrate that RGS4 can modulate mGluR responses in neurons, and they highlight a previously unknown mechanism for regulation of G-protein-coupled receptor signaling in the CNS.

Original languageEnglish (US)
Pages (from-to)905-913
Number of pages9
JournalJournal of Neuroscience
Volume18
Issue number3
DOIs
StatePublished - 1998

Keywords

  • G(α)- proteins
  • Hippocampus
  • Metabotropic glutamate receptor
  • RGS proteins
  • RGS4
  • Synaptic regulation
  • Xenopus

ASJC Scopus subject areas

  • Neuroscience(all)

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