Affiliated with Université Laval & CERVO Research Centre

Allosteric modulation of metabotropic glutamate receptors by chloride ions.

TitleAllosteric modulation of metabotropic glutamate receptors by chloride ions.
Publication TypeJournal Article
Year of Publication2015
AuthorsTora AS, Rovira X, Dione I, Bertrand H-O, Brabet I, De Koninck Y, Doyon N, Pin J-P, Acher F, Goudet C
JournalFASEB J
Volume29
Issue10
Pagination4174-88
Date Published2015 Oct
ISSN1530-6860
KeywordsAllosteric Regulation, Allosteric Site, Amino Acid Sequence, Animals, Binding Sites, Chlorides, Extracellular Space, HEK293 Cells, Humans, Models, Molecular, Mutation, Protein Binding, Protein Structure, Tertiary, Rats, Receptors, Metabotropic Glutamate, Sequence Homology, Amino Acid
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.

DOI10.1096/fj.14-269746
Alternate JournalFASEB J.
PubMed ID26116702
Grant List / / Canadian Institutes of Health Research / Canada