Identification of a serotonin/glutamate receptor complex implicated in psychosis.
Javier González-Maeso, Rosalind L Ang, Tony Yuen, Pokman Chan, Noelia V Weisstaub, Juan F López-Giménez, Mingming Zhou, Yuuya Okawa, Luís F. Callado, Graeme Milligan, Jay A Gingrich, Marta Filizola, J Javier Meana, Stuart C. Sealfon
Nature March 6, 2008 DOI: 10.1038/nature06612 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science study Peer reviewed |
|---|---|
| Population | Brain cortex tissue from human post-mortem subjects (schizophrenic and control) and animal models |
| Topics | Serotonin |
| Key points | The 5-HT2A receptor and mGluR2 form functional heteromeric complexes in the cortex; hallucinogen-specific signaling and behavioral responses are abolished by mGluR2 activation. In untreated schizophrenic post-mortem brains, 5-HT2A is upregulated and mGluR2 is downregulated, suggesting the complex may contribute to 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.