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Cell ; 147(5): 1011-23, 2011 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-22118459

RESUMEN

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.


Asunto(s)
Antipsicóticos/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal , Anfetaminas/farmacología , Animales , Clozapina/farmacología , Dimerización , Relación Dosis-Respuesta a Droga , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Metisergida/farmacología , Ratones , Oocitos , Canales de Potasio de Rectificación Interna/metabolismo , Xenopus
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