Cited by 313Receptor Mechanisms and SignalingNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs

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Fribourg, Miguel, Moreno, José L., Holloway, Terrell, Provasi, Davide, Baki, Lia, Mahajan, Rahul, Park, Gyu, Adney, Scott K. +14 more·2011·Cell

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.

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    From Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation (2013) · cites this paper as [30]

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  1. Patil ST Zhang L Martenyi F Lowe SL Jackson KA Andreev BV Avedisova AS Bardenstein LM Gurovich IY Morozova MA Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial Nat. Med 2007 13 1102 1107 17767166

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Authors
Fribourg, M., Moreno, J. L., Holloway, T., Provasi, D., Baki, L., Mahajan, R., Park, G., Adney, S. K., Hatcher, C., Eltit, J. M., Ruta, J. D., Albizu, L., Li, Z., Umali, A., Shim, J., Fabiato, A., MacKerell, A. D., Brezina, V., Sealfon, S. C., Filizola, M., González-Maeso, J., & Logothetis, D. E.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Virginia Commonwealth University (US)
  • University of Maryland, Baltimore (US)
Corresponding author
Logothetis, Diomedes E.
Venue
Cell
Publisher
Elsevier BV
Published
2011-11
Volume
147
Issue
5
Pages
1011-1023
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2029021490
Cited by
311
References
65
Citations by year
2026: 8 · 2025: 14 · 2024: 17 · 2023: 19 · 2022: 18 · 2021: 17 · 2020: 25 · 2019: 16 · 2018: 29 · 2017: 21 · 2016: 26 · 2015: 14 · 2014: 27 · 2013: 26 · 2012: 31
FWCI
11.31
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation
  • Vanderbilt University
  • Virginia Commonwealth University
  • National Alliance for Research on Schizophrenia and Depression
  • Dainippon Sumitomo Pharma
  • University of Crete
  • National Institutes of Health (MH091360)
  • National Heart, Lung, and Blood Institute (F30HL097582, HL 59949, R01HL059949)
  • National Institute of Mental Health (R56MH084894, MH091360, MH084894, R21MH091360, R01MH084894)
  • National Institute on Drug Abuse (SRC1DA02811202, K02DA026434, DA026434, R01DA026947)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
5-HT2A receptor, mGluR2, antipsychotic drugs, G protein signaling, clozapine, risperidone, ritanserin, methysergide, schizophrenia, dementia
MeSH terms
Amphetamines, Animals, Clozapine, Dose-Response Relationship, Drug, Frontal Lobe, Methysergide, Oocytes, Antipsychotic Agents, Xenopus, Signal Transduction, Receptors, Metabotropic Glutamate, Receptors, Adrenergic, beta-2, Dimerization, Potassium Channels, Inwardly Rectifying, Mice

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