RGS4 inhibits signaling by group I metabotropic glutamate receptors.

Saugstad JA, Marino MJ, Folk JA, Hepler JR, Conn PJ
J Neurosci. 1998 18 (3): 905-13

PMID: 9437012

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 Galpha subunits to inhibit cellular responses by G-protein-coupled receptors. RGS4 blocks Gq activation of phospholipase Cbeta and is expressed broadly in rat brain. The group I mGluRs (mGluRs 1 and 5) couple to Gq 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 trisphospate-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.

MeSH Terms (32)

Age Factors Animals Calcium Calcium-Calmodulin-Dependent Protein Kinases Calcium Channels Cell Membrane Chloride Channels Glioma G Protein-Coupled Inwardly-Rectifying Potassium Channels GTP-Binding Proteins Hippocampus Hybrid Cells Inositol 1,4,5-Trisphosphate Isoenzymes Mice Neurons Oocytes Patch-Clamp Techniques Phospholipase C beta Potassium Channels Potassium Channels, Inwardly Rectifying Proteins Rats Receptors, Metabotropic Glutamate Receptors, Muscarinic RGS Proteins RNA, Messenger Signal Transduction Synapses Tritium Type C Phospholipases Xenopus

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