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FASEB J. 2015 Oct;29(10):4174-88. doi: 10.1096/fj.14-269746. Epub 2015 Jun 26.

Allosteric modulation of metabotropic glutamate receptors by chloride ions.

Author information

1
*Institut de Génomique Fonctionnelle, CNRS, UMR 5203, Université de Montpellier, Montpellier, France; INSERM U1191, Montpellier, France; Centre de Recherche de l'Institut Universitaire en Santé Mentale du Québec and Université Laval, Québec, Canada; Biovia Dassault Systèmes, Orsay, France; and Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS, UMR 8601, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
2
*Institut de Génomique Fonctionnelle, CNRS, UMR 5203, Université de Montpellier, Montpellier, France; INSERM U1191, Montpellier, France; Centre de Recherche de l'Institut Universitaire en Santé Mentale du Québec and Université Laval, Québec, Canada; Biovia Dassault Systèmes, Orsay, France; and Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS, UMR 8601, Université Paris Descartes, Sorbonne Paris Cité, Paris, France francine.acher@parisdescartes.fr cyril.goudet@igf.cnrs.fr.

Abstract

Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl(-)) is known to directly bind and regulate the function of different actors of neuronal activity, and several studies have pointed to the possible modulation of mGluRs by Cl(-). Herein, we demonstrate that Cl(-) behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 ± 0.33 μM on metabotropic glutamate (mGlu) 4 receptors in high-Cl(-) buffer, signaling activity was almost abolished in low Cl(-) in cell-based assays. Cl(-) potency was 78.6 ± 3.5 mM. Cl(-) possesses a high positive cooperativity with glutamate (Hill slope ≈6 on mGlu4), meaning that small variations in [Cl(-)] lead to large variations in glutamate action. Using molecular modeling and mutagenesis, we have identified 2 well-conserved Cl(-) binding pockets in the extracellular domain of mGluRs. Moreover, modeling of activity-dependent Cl(-) variations at GABAergic synapses suggests that these variations may be compatible with a dynamic modulation of the most sensitive mGluRs present in these synapses. Taken together, these data reveal a necessary role of Cl(-) for the glutamate activation of many mGluRs. Exploiting Cl(-) binding pockets may yield to the development of innovative regulators of mGluR activity.

KEYWORDS:

GABA; GPCR; PAM; allostery; anion

PMID:
26116702
DOI:
10.1096/fj.14-269746
[Indexed for MEDLINE]

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