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

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TitleDecoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.
Publication TypeJournal Article
Year of Publication2011
AuthorsFribourg, 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, Brezina, V, Sealfon, SC, Filizola, M, González-Maeso, J, Logothetis, DE
JournalCell
Volume147
Issue5
Pagination1011-23
Date Published2011 Nov 23
ISSN1097-4172
KeywordsAmphetamines, Animals, Antipsychotic Agents, Clozapine, Dimerization, Dose-Response Relationship, Drug, Frontal Lobe, Methysergide, Mice, Oocytes, Potassium Channels, Inwardly Rectifying, Receptors, Adrenergic, beta-2, Receptors, Metabotropic Glutamate, Signal Transduction, Xenopus
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.

DOI10.1016/j.cell.2011.09.055
Alternate JournalCell
PubMed ID22118459
PubMed Central IDPMC3255795
Grant ListR21 MH091360 / MH / NIMH NIH HHS / United States
F30 HL097582 / HL / NHLBI NIH HHS / United States
1R01DA02694702 / DA / NIDA NIH HHS / United States
5R01MH084894 / MH / NIMH NIH HHS / United States
MH091360 / MH / NIMH NIH HHS / United States
R01 HL059949 / HL / NHLBI NIH HHS / United States
F30HL097582 / HL / NHLBI NIH HHS / United States
MH084894 / MH / NIMH NIH HHS / United States
K02 DA026434 / DA / NIDA NIH HHS / United States
R01 MH084894 / MH / NIMH NIH HHS / United States
SRC1DA02811202 / DA / NIDA NIH HHS / United States
DA026434 / DA / NIDA NIH HHS / United States
R56 MH084894 / MH / NIMH NIH HHS / United States
HL59949 / HL / NHLBI NIH HHS / United States
R01 HL059949-15 / HL / NHLBI NIH HHS / United States