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5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling

Abstract : 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.
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Soumis le : vendredi 8 novembre 2019 - 16:33:09
Dernière modification le : mercredi 14 octobre 2020 - 04:09:49
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Murat et al (2018) Mol Psy.pdf
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Samy Murat, Mathilde Bigot, Jonathan Chapron, Gabriele König, Evi Kostenis, et al.. 5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling. Molecular Psychiatry, Nature Publishing Group, 2019, 24 (11), pp.1610-1626. ⟨10.1038/s41380-018-0069-6⟩. ⟨hal-02356293⟩

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