Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

NEUROPHARMACOLOGY

卷:140

Article

Tora, Amelie S.¹  Rovira, Xavier^1,5  Cao, Anne-Marinette²  Cabaye, Alexandre³  Olofsson, Linnea²  Malhaire, Fanny¹  Scholler, Pauline¹  Baik, Hayeon¹  Van Eeckhaut, Ann⁴  Smolders, Ilse⁴  Rondard, Philippe¹  Margeat, Emmanuel²  Acher, Francine³  Pin, Jean-Philippe¹  Goudet, Cyril¹ 

[1] Univ Montpellier, CNRS, INSERM, IGF, F-34094 Montpellier, France

[2] Univ Montpellier, CNRS, INSERM, CBS, F-34094 Montpellier, France

[3] Univ Paris 05, Sorbonne Paris Cite, Lab Chim & Biochim Pharmacol & Toxicol, CNRS,UMR8601, 45 Rue St Peres, F-75270 Paris 6, France

[4] VUB, Ctr Neurosci C4N, Res Grp Expt Pharmacol EFAR FASC, B-1090 Brussels, Belgium

[5] Cent Univ Catalonia, Univ Vic, Tissue Repair & Regenerat Lab, Mol Photopharmacol Res Grp, C La Laura 13, Vic 08500, Spain

关键词: Glutamate;    Receptor;    Chloride;    Constitutive activity;    Allostery;    GPCR;   

DOI  :  10.1016/j.neuropharm.2018.08.011

来源: Elsevier

【 摘 要 】

Due to the essential roles of glutamate, detection and response to a large range of extracellular concentrations of this excitatory amino acid are necessary for the fine-tuning of brain functions. Metabotropic glutamate receptors (mGluRs) are implicated in shaping the activity of many synapses in the central nervous system. Among the eight mGluR subtypes, there is increasing interest in studying the mG1u(3) receptor which has recently been linked to various diseases, including psychiatric disorders. This receptor displays striking functional properties, with a high and, often, full basal activity, making its study elusive in heterologous systems. Here, we demonstrate that Cl- ions exert strong positive allosteric modulation of glutamate on the mG1u(3) receptor. We have also identified the molecular and structural determinants lying behind this allostery: a unique interactive chloride-lock network. Indeed, Cl-ions dramatically stabilize the glutamate-induced active state of the extracellular domain of the mG1u(3) receptor. Thus, the mG1u(3) receptors' large basal activity does not correspond to a constitutive activity in absence of agonist. Instead, it results mostly from a Cl-mediated amplified response to low ambient glutamate concentrations, such as those measured in cell media. This strong interaction between glutamate and Cl ions allows the mG1u(3) receptor to sense and efficiently react to sub-micromolar concentrations of glutamate, making it the most sensitive member of mGluR family.

【 授权许可】

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