A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor Alters 5-HT2A Receptor Signaling in a Heteromeric Complex

Atypical antipsychotic drugs targeting the Gq-coupled serotonin 5-HT2A receptor (2AR) are widely used in the treatment of schizophrenia, whereas recent studies point to a new class of potential antipsychotic drugs targeting the Gi-coupled metabotropic glutamate 2 receptor (mGluR2). A physical and functional interaction between the two receptors in cortical pyramidal neurons has been demonstrated.Using heterologously expressed receptors in Xenopus oocytes, we have previously shown that the heteromeric mGluR2/2AR complex integrates the actions of serotonergic and glutamatergic ligands, modulating the balance between Gi and Gq signaling in a way that can be used to predict the psychoactive properties of these drugs.Selective positive allosteric modulators (PAMs) of mGluR2 that bind to the transmembrane region of the receptor have shown efficacy in rodent models predictive of antipsychotic activity. Here we show that the mGluR2 PAM, LY487379 (or simply LY48) not only enhances glutamate-induced Gi signaling but also shows crosstalk by reducing 5-HT-induced Gq signaling. PAMs offer a promising therapeutic approach for the activation of GPCRs because they preserve the physiologic pattern of receptor signaling and are less likely to cause receptor desensitization and/or down regulation than synthetic agonists.