Metabotropic glutamate receptor 2 (mGlu2) is a G protein-coupled receptor expressed in the central nervous system and canonically coupled to Gi/o protein. mGlu2 receptor is the main target of a new generation of antipsychotics which showed unprecedent efficiency on negative and cognitive symptoms of Schizophrenia, which were so far resisting to actual antipsychotics. However, the molecular mechanisms regulating the antipsychotic properties of mGlu2 receptor stimulation remain unclear. In a recent interactomic screen (Philibert et al., Science Advances, 2024), we demonstrated that endogenous mGlu2 receptor interacts physically with a kinase called Salt-Induced kinase 3 (SIK3) in mouse prefrontal cortex. Recently, SIK3 was shown to be negatively regulated by cAMP-dependent PKA through the phosphorylation of three different sites. In this work, we further validated the specific interaction of the two proteins and evaluated the effect of mGlu2 receptor stimulation on SIK3 activity. SIK3 activation by mGlu2 receptor is achieved through a decreased phosphorylation of inhibitory PKA sites following the activation of the Gi/o protein. Then, we showed that SIK3 phosphorylates mGlu2 at the first intracellular loop of the receptor. Phosphorylation site mutation into Alanine showed that this phosphorylation negatively controls the mGlu2 receptor response to its orthosteric agonist LY379268. In conclusion, we discovered a new signaling pathway for mGlu2 receptor that exerts a negative feedback on the receptor activity. We are now evaluating the effects of SIK3 pharmacological inhibition on the behavioral response to mGlu2 agonist in a mouse model model of Schizophrenia.