RGS4 inhibits signaling by group I metabotropic glutamate receptors

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

Research output: Contribution to journalArticle

112 Citations (Scopus)

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
StatePublished - 1998
Externally publishedYes

Fingerprint

Metabotropic Glutamate Receptors
Type C Phospholipases
G-Protein-Coupled Receptors
RGS Proteins
GTPase-Activating Proteins
Neurons
Heterotrimeric GTP-Binding Proteins
Calcium Chloride
Protein Subunits
Inositol
Xenopus
GTP-Binding Proteins
Synaptic Transmission
Oocytes
Potassium
Membranes
Brain
Proteins
metabotropic glutamate receptor type 1

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Saugstad, J., Marino, M. J., Folk, J. A., Hepler, J. R., & Conn, P. J. (1998). RGS4 inhibits signaling by group I metabotropic glutamate receptors. Journal of Neuroscience, 18(3), 905-913.

RGS4 inhibits signaling by group I metabotropic glutamate receptors. / Saugstad, Julie; Marino, Michael J.; Folk, Julie A.; Hepler, John R.; Conn, P. Jeffrey.

In: Journal of Neuroscience, Vol. 18, No. 3, 1998, p. 905-913.

Research output: Contribution to journalArticle

Saugstad, J, Marino, MJ, Folk, JA, Hepler, JR & Conn, PJ 1998, 'RGS4 inhibits signaling by group I metabotropic glutamate receptors', Journal of Neuroscience, vol. 18, no. 3, pp. 905-913.
Saugstad, Julie ; Marino, Michael J. ; Folk, Julie A. ; Hepler, John R. ; Conn, P. Jeffrey. / RGS4 inhibits signaling by group I metabotropic glutamate receptors. In: Journal of Neuroscience. 1998 ; Vol. 18, No. 3. pp. 905-913.
@article{68c5fade010a471288b3a046796ef435,
title = "RGS4 inhibits signaling by group I metabotropic glutamate receptors",
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.",
keywords = "G(α)- proteins, Hippocampus, Metabotropic glutamate receptor, RGS proteins, RGS4, Synaptic regulation, Xenopus",
author = "Julie Saugstad and Marino, {Michael J.} and Folk, {Julie A.} and Hepler, {John R.} and Conn, {P. Jeffrey}",
year = "1998",
language = "English (US)",
volume = "18",
pages = "905--913",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "3",

}

TY - JOUR

T1 - RGS4 inhibits signaling by group I metabotropic glutamate receptors

AU - Saugstad, Julie

AU - Marino, Michael J.

AU - Folk, Julie A.

AU - Hepler, John R.

AU - Conn, P. Jeffrey

PY - 1998

Y1 - 1998

N2 - 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.

AB - 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.

KW - G(α)- proteins

KW - Hippocampus

KW - Metabotropic glutamate receptor

KW - RGS proteins

KW - RGS4

KW - Synaptic regulation

KW - Xenopus

UR - http://www.scopus.com/inward/record.url?scp=0031892347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031892347&partnerID=8YFLogxK

M3 - Article

C2 - 9437012

AN - SCOPUS:0031892347

VL - 18

SP - 905

EP - 913

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 3

ER -