Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl 2 ) 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 2 . Herein, we demonstrate that Cl 2 behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 6 0.33 mM on metabotropic glutamate (mGlu) 4 receptors in high-Cl 2 buffer, signaling activity was almost abolished in low Cl 2 in cell-based assays.

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 mGlu 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 mGlu 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 mGlu receptor. Thus, the mGlu receptors' large basal activity does not correspond to a constitutive activity in absence of agonist. Instead, it results mostly from a Clmediated amplified response to low ambient glutamate concentrations, such as those measured in cell media. This strong interaction between glutamate and Cl ions allows the mGlu receptor to sense and efficiently react to sub-micromolar concentrations of glutamate, making it the most sensitive member of mGluR family.