151. 5-HT2Areceptor-dependent phosphorylation of mGlu2receptor at Serine 843 promotes mGlu2receptor-operated Gi/osignaling
- Author
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Murat, Samy, Bigot, Mathilde, Chapron, Jonathan, König, Gabriele M., Kostenis, Evi, Battaglia, Giuseppe, Nicoletti, Ferdinando, Bourinet, Emmanuel, Bockaert, Joël, Marin, Philippe, and Vandermoere, Franck
- Abstract
The serotonin 5-HT2Aand glutamate mGlu2receptors 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-HT2Areceptor upon the phosphorylation pattern of mGlu2receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843was enhanced upon mGlu2receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2Areceptor. Likewise, administration of LY379268 increased mGlu2receptor phosphorylation at Ser843in prefrontal cortex of wild-type mice but not 5-HT2A−/−mice. Exposure of HEK-293 cells co-expressing mGlu2and 5-HT2Areceptors to 5-HT also increased Ser843phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843phosphorylation elicited by 5-HT2Areceptor stimulation was prevented by the mGlu2receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2Areceptor antagonist M100907. Mutation of Ser843into alanine strongly reduced Gi/osignaling elicited by mGlu2or 5-HT2Areceptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2receptor phosphorylation at Ser843as a key molecular event that underlies the functional crosstalk between both receptors.
- Published
- 2019
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