How to Design a Better Antipsychotic?

Science Signaling  06 Dec 2011:
Vol. 4, Issue 202, pp. ec342
DOI: 10.1126/scisignal.4202ec342

Psychosis, a mental disorder in which afflicted individuals lose touch with reality, can be treated with typical neuroleptics, which target the dopamine D2 receptor, or with newer atypical neuroleptics, which have other targets, including the serotonin 5-HT2A receptor (2AR) (see Kondo and Sawa). The 2AR forms a heteromeric complex with the metabotropic glutamate 2 receptor (mGluR2), and Fribourg et al. investigated how antipsychotics affected the signaling properties of this heteromer. In a Xenopus oocyte heterologous expression system, coexpression of mGluR2 with the 2AR reduced Gq activity (evoked by serotonin-mediated activation of the 2AR activation) compared with expression of the 2AR alone. In addition, coexpression increased Gi activity (evoked by glutamate-mediated activation of mGluR2) compared with expression of mGluR2 alone. To describe the combined change in Gi activity (ΔGi) and Gq activity (ΔGq), the authors used a metric they called the balance index (BI, which equaled ΔGi – ΔGq). In oocytes expressing the 2AR-mGluR2 heteromer, glutamate signaling through mGluR2 was decreased by DOI, a strong agonist of the 2AR, and increased by clozapine, an atypical neuroleptic that is an inverse agonist of the 2AR. Compared with DOI or a neutral antagonist of the 2AR, clozapine had the highest BI because it produced the largest increase in Gi signaling and the largest decrease in Gq signaling. Compared with 2AR homomers, heteromerization with mGluR2 decreased serotonin-mediated activation of Gq through the 2AR, which was further decreased by LY37, a strong agonist of mGluR2. In contrast, LY34, an inverse agonist of mGluR2, restored serotonin-mediated activation of Gq in heteromer-expressing cells to an extent comparable to 2AR homomer-expressing cells. Effectiveness of an antipsychotic in human patients (irrespective of whether it targeted the 2AR or mGluR2) correlated with higher BI values or resulted in higher Gi activity relative to Gq activity. In membrane preparations from mouse frontal cortex, clozapine treatment increased Gi signaling in response to glutamate and LY37 increased Gq activity in response to serotonin. The N-methyl-D-aspartate receptor antagonist MK801 induces increased locomotion in mice and is used as a model of schizophrenia (a psychotic condition). The MK801-induced increase in locomotor activity was attenuated by clozapine or LY37 in wild-type mice, but the effect of clozapine was lost in mice lacking GluR2 and that of LY37 was lost in mice lacking the 2AR. Thus, effective antipsychotics could be identified by their effect on signaling through the 2AR-mGluR2 heteromer.

M. Fribourg, J. L. Moreno, T. Holloway, D. Provasi, L. Baki, R. Mahajan, G. Park, S. K. Adney, C. Hatcher, J. M. Eltit, J. D. Ruta, L. Albizu, Z. Li, A. Umali, J. Shim, A. Fabiato, A. D. MacKerell Jr., V. Brezina, S. C. Sealfon, M. Filizola, J. González-Maeso, D. E. Logothetis, Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147, 1011–1023 (2011). [PubMed]

M. Kondo, A. Sawa, Anti-/propsychotic drug signaling via heteromeric GPCRs—A balancing act? Cell 147, 964–965 (2011). [PubMed]