Allosteric modulation of metabotropic glutamate receptors by chloride ions

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 mM 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 approximate to 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.