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Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs |
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| Authors: | Fribourg Miguel Moreno José L Holloway Terrell Provasi Davide Baki Lia Mahajan Rahul Park Gyu Adney Scott K Hatcher Candice Eltit José M Ruta Jeffrey D Albizu Laura Li Zheng Umali Adrienne Shim Jihyun Fabiato Alexandre MacKerell Alexander D Brezina Vladimir Sealfon Stuart C Filizola Marta González-Maeso Javier Logothetis Diomedes E |
| Affiliation: | 1 Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA 2 Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA 3 Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA 4 Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA 5 Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, NY 10029, USA 6 Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA 7 Pharmaceutical Sciences Department, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA 8 Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA |
| Abstract: | Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) 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 G(i)-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. |
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