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Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes
Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K(+) channel, GIRK, is activated by the βγ subunits of G(i) proteins and is widely expressed in the brain. We investigated whether an interaction between mGluR...
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
1997
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219433/ https://www.ncbi.nlm.nih.gov/pubmed/9101406 |
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author | Sharon, Dahlia Vorobiov, Dmitry Dascal, Nathan |
author_facet | Sharon, Dahlia Vorobiov, Dmitry Dascal, Nathan |
author_sort | Sharon, Dahlia |
collection | PubMed |
description | Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K(+) channel, GIRK, is activated by the βγ subunits of G(i) proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by G(i)/G(o)-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the G(q) class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca(2+) chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-μ. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a G(i)/G(o) protein. The observed modulations may be involved in the mGluRs' effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C–activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to G(q) are inefficient in activating GIRK. |
format | Text |
id | pubmed-2219433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1997 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22194332008-04-22 Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes Sharon, Dahlia Vorobiov, Dmitry Dascal, Nathan J Gen Physiol Article Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K(+) channel, GIRK, is activated by the βγ subunits of G(i) proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by G(i)/G(o)-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the G(q) class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca(2+) chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-μ. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a G(i)/G(o) protein. The observed modulations may be involved in the mGluRs' effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C–activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to G(q) are inefficient in activating GIRK. The Rockefeller University Press 1997-04-01 /pmc/articles/PMC2219433/ /pubmed/9101406 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Sharon, Dahlia Vorobiov, Dmitry Dascal, Nathan Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title | Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title_full | Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title_fullStr | Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title_full_unstemmed | Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title_short | Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K(+) Channel, GIRK, in Xenopus Oocytes |
title_sort | positive and negative coupling of the metabotropic glutamate receptors to a g protein–activated k(+) channel, girk, in xenopus oocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219433/ https://www.ncbi.nlm.nih.gov/pubmed/9101406 |
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