Reference - Detail
| RRC ID | 12686 |
|---|---|
| Author | Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD Jr, Brezina V, Sealfon SC, Filizola M, González-Maeso J, Logothetis DE. |
| Title | Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. |
| Journal | 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. |
| Volume | 147(5) |
| Pages | 1011-23 |
| Published | 2011-11-23 |
| DOI | 10.1016/j.cell.2011.09.055 |
| PII | S0092-8674(11)01272-4 |
| PMID | 22118459 |
| PMC | PMC3255795 |
| MeSH | Amphetamines / pharmacology Animals Antipsychotic Agents / pharmacology* Clozapine / pharmacology Dimerization Dose-Response Relationship, Drug Frontal Lobe / drug effects Frontal Lobe / metabolism Methysergide / pharmacology Mice Oocytes Potassium Channels, Inwardly Rectifying / metabolism Receptors, Adrenergic, beta-2 / metabolism* Receptors, Metabotropic Glutamate / metabolism* Signal Transduction* Xenopus |
| IF | 38.637 |
| Times Cited | 168 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 61 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC01351 |