Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs
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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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Several recent studies of drugs acting at cell surface receptor targets show that the activation mechanisms responsible for their cellular and systemic effects are more complex than accounted for by their classical pharmacological profiles.
“Several recent studies of drugs acting at cell surface receptor targets show that the activation mechanisms responsible for their cellular and systemic effects are more complex than accounted for by their classical pharmacological profiles (30 -32).”
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]
Temporal pattern encoding relieves the cellular information bottleneck, where many stimuli must signal through few intracellular pathways to generate diverse and specific cellular responses, but complicates the relationship between synthetic target modulators and their cellular and clinical effects.
“Temporal pattern encoding relieves the cellular information bottleneck, where many stimuli must signal through few intracellular pathways to generate diverse and specific cellular responses (30 -32) but complicates the relationship between synthetic target modulators and their cellular and clinical effects.”
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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“For disorders such as schizophrenia and dementia, metabotropic glutamate 2 receptor/serotonin 2A receptor– mediated changes in Gi and Gq activity could affect the psychoactive behavioral effects of a variety of pharmacological compounds (Fribourg et al. 2011).”
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Self-citation
- 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.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 147
- Issue
- 5
- Pages
- 1011-1023
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3255795
- 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
- bronze
- doi.org
- Licence
- 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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