Structural basis of the activation of metabotropic glutamate receptor 3

Dear Editor, Glutamate is used by most synapses in the brain and responsible for fast excitatory transmission,thus playing impor-tant roles in excitotoxicity and ammonium detoxification in the brain.1 Eight G protein-coupled metabotropic glutamate recep-tors(mGlus)are essential in sensing glutamate concentrations from the ten nanomolar to ten millimolar range in the brain.2 The mGlu3 is in high sequence homology with mGlu2,but mGlu3 is of greater interest because it is responsible for the detection of very low concentrations of glutamate.2 The mGlu3 is found in astrocytes and in both pre-and post-synaptic elements in neurons,whereas mGlu2 is mainly distributed in neurons,particularly in the preterminal region of axons,far from the active zone of neurotransmitter release3.Accumulating evidence supports a role of mGlu3 not only in maintaining synaptic homeostasis but also in promoting neuronal and astrocyte survival in several pathological conditions.4 The mGlu3 has garnered attention as a potent therapeutic target for both psychiatric disorders and neurodegenerative diseases such as schizophrenia,Alzheimer's disease,anxiety,depression,pain and addiction.5,6 Polymorphic variants of the gene encoding mGlu3 are linked to schizophrenia.Furthermore,recent studies have suggested that negative allosteric modulators(NAMs)of both mGlu3 and mGlu2 induced rapid antidepressant-like effects through related but divergent mechanisms of action.7 Moreover,the high sequence homology of mGlu3 and mGlu2 restricts the development of selective ligands,which demands the structures of mGlu3.