title: Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.
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.
authors: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: Miguel
authors: M
authors: Fribourg
authors: José L
authors: JL
authors: Moreno
authors: Terrell
authors: T
authors: Holloway
authors: Davide
authors: D
authors: Provasi
authors: Lia
authors: L
authors: Baki
authors: Rahul
authors: R
authors: Mahajan
authors: Gyu
authors: G
authors: Park
authors: Scott K
authors: SK
authors: Adney
authors: Candice
authors: C
authors: Hatcher
authors: José M
authors: JM
authors: Eltit
authors: Jeffrey D
authors: JD
authors: Ruta
authors: Laura
authors: L
authors: Albizu
authors: Zheng
authors: Z
authors: Li
authors: Adrienne
authors: A
authors: Umali
authors: Jihyun
authors: J
authors: Shim
authors: Alexandre
authors: A
authors: Fabiato
authors: Alexander D
authors: AD
authors: MacKerell
authors: Vladimir
authors: V
authors: Brezina
authors: Stuart C
authors: SC
authors: Sealfon
authors: Marta
authors: M
authors: Filizola
authors: Javier
authors: J
authors: González-Maeso
authors: Diomedes E
authors: DE
authors: Logothetis
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D009865:Oocytes; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D014981:Xenopus
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D024661:Potassium Channels, Inwardly Rectifying; D018343:Receptors, Adrenergic, beta-2; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D003024:Clozapine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D008784:Methysergide