Identification of a serotonin/glutamate receptor complex implicated in psychosis.
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.
González-Maeso
Javier
J
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu
Ang
Rosalind L
RL
Yuen
Tony
T
Chan
Pokman
P
Weisstaub
Noelia V
NV
López-Giménez
Juan F
JF
Zhou
Mingming
M
Okawa
Yuuya
Y
Callado
Luis F
LF
Milligan
Graeme
G
Gingrich
Jay A
JA
Filizola
Marta
M
Meana
J Javier
JJ
Sealfon
Stuart C
SC
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
D006213:Hallucinogens; D046912:Multiprotein Complexes; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2