Résumé
The serotonin 5-HT 2A and glutamate mGlu 2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT 2A receptor upon the phosphorylation pattern of mGlu 2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu 2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser 843 was enhanced upon mGlu 2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT 2A receptor. Likewise, administration of LY379268 increased mGlu 2 receptor phosphorylation at Ser 843 in prefrontal cortex of wild-type mice but not 5-HT 2A −/− mice. Exposure of HEK-293 cells co-expressing mGlu 2 and 5-HT 2A receptors to 5-HT also increased Ser 843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser 843 phosphorylation elicited by 5-HT 2A receptor stimulation was prevented by the mGlu 2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT 2A receptor antagonist M100907. Mutation of Ser 843 into alanine strongly reduced G i/o signaling elicited by mGlu 2 or 5-HT 2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu 2 receptor phosphorylation at Ser 843 as a key molecular event that underlies the functional crosstalk between both receptors.