Unifying antipsychotic drugs

The antipsychotic drugs clozapine and risperidone bind to and block the serotonin G protein–coupled receptor (GPCR) 2AR. Other serotonin antagonists, such as ritanserin and methysergide, also inhibit 2AR function, but for unknown reasons do not have antipsychotic effects. Now, Javier Gonzalez-Maeso, Diomedes Logothetis and colleagues report that signaling mediated by a heteromeric complex between 2AR and another GPCR, the metabotropic glutamate 2 receptor (mGluR2), is important for transducing the effects of antipsychotic drugs (Cell 147, 1011–1023, 2011 ). 2AR responds to the neurotransmitter serotonin and is coupled to the G_q G protein, whereas mGluR2 responds to the neurotransmitter glutamate and is coupled to the G_i G protein. Signaling mediated by the mGluR2-2AR heteromeric complex differs from signaling from the individual receptors. Specifically, the heteromeric complex enhances glutamate signaling through G_i and lowers serotonin signaling through G_q. To quantify these signaling differences, the authors used a metric called the balance index (BI), with BI = change in G_i activity (ΔG_i) – change in G_q activity (ΔG_q). The most effective antipsychotic drugs had the highest BI measurements, regardless of whether the drug targeted 2AR or mGluR2. BI measurements could also predict the psychoactive effects of a variety of compounds, suggesting that these findings may result in the identification of more effective therapeutics for schizophrenia and dementia.