Synergy between Gq and Gi proteins for the antipsychotic-like effects of mGlu2 receptors

The capacity of one G protein–coupled receptor (GPCR) to modulate signaling outputs of another is a phenomenon with potential implications for neuron function and therapeutic action. Notably, Gi/o-coupled receptors have been shown to generate calcium signals after costimulation of Gq-coupled receptors, an effect resulting from a crosstalk between signaling cascades. But the relevance for brain function and for therapeutic applications remains largely unclear. Here we show that Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptors can generate calcium signals in neurons. It results from either agonist activation or constitutive activity of a Gq-coupled receptor endogenously coexpressed with mGlu2, independently of dimerization. Specifically, the constitutively active platelet-activating factor receptor (PAFR) plays an essential role in mGlu2-calcium signaling in hippocampal neurons, an effect largely inhibited by PAFR inverse agonists and genetic variants. This mGlu2-PAFR crosstalk is required for the cognitive and behavioral rescue produced by mGlu2 agonists in a mouse model of NMDA receptor hypofunction. These data highlight the complexity of GPCR signaling and provide key insights on therapeutic strategies for psychiatric disorders.