title: Identification of a serotonin/glutamate receptor complex implicated in psychosis.
abstract: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Ang
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.forename: Pokman
authors.initials: P
authors.lastname: Chan
authors.forename: Noelia V
authors.initials: NV
authors.lastname: Weisstaub
authors.forename: Juan F
authors.initials: JF
authors.lastname: López-Giménez
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhou
authors.forename: Yuuya
authors.initials: Y
authors.lastname: Okawa
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Jay A
authors.initials: JA
authors.lastname: Gingrich
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D006213:Hallucinogens / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D006213:Hallucinogens; D046912:Multiprotein Complexes; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2