RGS4 inhibits signaling by group I metabotropic glutamate receptors.
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.
Saugstad
J A
JA
Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA.
Marino
M J
MJ
Folk
J A
JA
Hepler
J R
JR
Conn
P J
PJ
D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology; D018118:Chloride Channels / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005910:Glioma; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology; D006822:Hybrid Cells / Q000737:chemistry / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020710:RGS Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000201:enzymology; D014316:Tritium; D010738:Type C Phospholipases / Q000378:metabolism; D014981:Xenopus
D015220:Calcium Channels; D018118:Chloride Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007527:Isoenzymes; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011506:Proteins; D020710:RGS Proteins; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D014316:Tritium; C098799:RGS4 protein; D015544:Inositol 1,4,5-Trisphosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D019204:GTP-Binding Proteins; D002118:Calcium