Glutamatergic and serotoninergic systems have been implicated in psychotic disorders. González-Maeso and colleagues, writing in Nature, show that 5-hydroxytryptamine (5-HT) 2A receptors (5-HT2AR) — through which many existing antipsychotic drugs act — and metabotropic type-2 glutamate receptors (mGluR2) — which are potential new anti-psychotic targets — form complexes that might be involved in schizophrenia.
It has been suggested that many members of the G-protein-coupled receptor (GPCR) family can exist as oligomeric complexes. Two findings led the authors to posit that this could occur with 5-HT2AR and mGluR2: mRNA for the two receptors was colocalized in mouse neuronal cultures, and mGluR2 protein levels were decreased in 5-HT2AR-knockout mice. Evidence for the existence of 5-HT2AR–mGluR2 complexes was obtained by co-immunoprecipitation and resonance-energy-transfer studies.
Competition-binding experiments, in which an mGluR2/3 agonist increased the affinity of three hallucinogenic 5-HT2AR agonists for the 5-HT-binding site, and in which a 5-HT2AR agonist decreased the affinity of the three mGluR2/3 agonists for the glutamate-binding site, suggested that the 5-HT2AR–mGluR2 complex might serve to integrate serotonin and glutamate signalling. Furthermore, by measuring the regulation of specific G-protein subunits, the receptor complex was shown to modulate G-protein coupling. Using molecular chimaeras of mGluR2 and mGluR3 — the latter of which did not form complexes — the authors demonstrated that the segment of mGluR2 that contains transmembrane helices 4 and 5 was necessary and sufficient for the formation of a complex with 5-HT2AR.
In the mouse cortex and in primary cortical cultures, the induction of early growth response gene 2 — a specific marker for hallucinogen signalling through 5-HT2AR — was blocked by an mGluR2/3 agonist that also suppressed the induction of hallucinogen-specific head-twitch behaviour in vivo. This suggested that the 5-HT2AR–mGluR2 complex might be important for hallucinogen signalling and behaviour.
As the neuropsychological effects of hallucinogenic drugs present commonalities with the psychosis of schizophrenia, the authors investigated whether the components of the 5-HT2AR–mGluR2 signalling complex were altered in the cortex of subjects with schizophrenia. Drug-naïve schizophrenic subjects showed increased 5-HT2AR levels and decreased mGluR2 levels. This, combined with the observation that activation of the mGluR2 component of the 5-HT2AR–mGluR2 complex eliminates the hallucinogen-specific signalling, suggests that the increased 5-HT2AR and decreased mGluR2 found in the brain in schizophrenia might predispose to a hallucinogenic pattern of signalling.
Although further work is needed to investigate whether the 5-HT2AR–mGluR2 complex could be targeted for the treatment of psychosis, this study provides evidence of a GPCR complex with functional relevance and therapeutic potential.
ORIGINAL RESEARCH PAPER
González-Maeso, J. et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008)
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Harrison, C. Double GPCR trouble. Nat Rev Neurosci 9, 253 (2008). https://doi.org/10.1038/nrn2362