Cell：研究将加快强效抗精神病药的研发

Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs

Miguel Fribourg, José L. Moreno, Terrell Holloway, Davide Provasi, Lia Baki, Rahul Mahajan, Gyu Park, Scott K. Adney, Candice Hatcher, José M. Eltit, Jeffrey D. Ruta, Laura Albizu, Zheng Li, Adrienne Umali, Jihyun Shim, Alexandre Fabiato, Alexander D. MacKerell, Vladimir Brezina, Stuart C. Sealfon, Marta Filizola, Javier González-Maeso, Diomedes E.

Highlights Endogenous signals via 2AR/mGluR2 enhance Gi and reduce Gq signaling Atypical and glutamate antipsychotics promote high Gi to Gq activity Psychedelics signal via 2AR/mGluR2 to decrease the Gi to Gq difference The balance index explains the basis for combined antipsychotics therapy Summary Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT2A G protein-coupled receptor (GPCR), the 2AR, which signals via a Gq heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the Gi-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.