Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2.

摘要: Background and Purpose The activation of the metabotropic glutamate receptor 2 (mGlu2) reduces glutamatergic transmission in brain regions where excess excitatory signalling is implicated disorders such as anxiety schizophrenia. Positive allosteric modulators (PAMs) can provide a fine-tuned potentiation these receptors' function are being investigated novel therapeutic approach. An extensive set mutant human mGlu2 receptors were used to investigate molecular determinants that important for positive modulation at this receptor. Experimental Approach Site-directed mutagenesis, binding functional assays employed identify amino acids activity nine PAMs. The data from radioligand mutagenesis studies with computational docking predict mode an model based on recent structure mGlu1 receptor. Key Results New TM3 (R635, L639, F643), TM5 (L732) TM6 (W773, F776) identified first time playing role PAMs. Conclusions Implications This study furthers our understanding contribute improved future design