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Allosteric modulation of metabotropic glutamate receptors by chloride ions
Author(s) -
Tora Amélie S.,
Rovira Xavier,
Dione Ibrahima,
Bertrand HuguesOlivier,
Brabet Isabelle,
De Koninck Yves,
Doyon Nicolas,
Pin JeanPhilippe,
Acher Francine,
Goudet Cyril
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-269746
Subject(s) - metabotropic glutamate receptor , metabotropic glutamate receptor 2 , allosteric regulation , metabotropic glutamate receptor 5 , chemistry , glutamate receptor , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 7 , metabotropic receptor , allosteric modulator , metabotropic glutamate receptor 3 , biophysics , biochemistry , receptor , biology
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 ã6 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 manymGluRs. Exploiting Cl ‐ binding pockets may yield to the development of innovative regulators of mGluR activity.—Tora, A. S., Rovira, X., Dione, I., Bertrand, H.‐O., Brabet, I., De Koninck, Y., Doyon, N., Pin, J.P., Acher, F., Goudet, C. Allosteric modulation of metabotropic glutamate receptors by chloride ions. FASEB J. 29, 4174‐4188 (2015). www.fasebj.org