Allosteric modulation of metabotropic glutamate receptors by chloride ions

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
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https://hal.umontpellier.fr/hal-02065116
Contributeur : Mélanie Karli <>
Soumis le : mardi 12 mars 2019 - 14:20:18
Dernière modification le : mardi 28 mai 2019 - 14:12:02

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Amélie Tora, Xavier Rovira, Ibrahima Dione, Hugues-Olivier Bertrand, Isabelle Brabet, et al.. Allosteric modulation of metabotropic glutamate receptors by chloride ions. FASEB Journal, Federation of American Society of Experimental Biology, 2015, 29 (10), pp.4174-4188. ⟨10.1096/fj.14-269746⟩. ⟨hal-02065116⟩

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