Allosteric signaling through an mGlu2 and 5-HT_2A heteromeric receptor complex and its potential contribution to schizophrenia

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the G_q/11-coupled serotonin 5-HT₂A receptor and the G_i/o-coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT_2A heteromers with an mGlu2 agonist led to activation of G_q/11 proteins by the 5-HT₂A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to G _i/o proteins, and we determined the relative location of the G_i/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of G_q/11, but not G_i/o, was reduced in the frontal cortex of 5-HT_2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.