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

Samy Murat, Mathilde Bigot, Jonathan Chapron, Gabriele M. König, Evi Kostenis, Giuseppe Battaglia, Ferdinando Nicoletti, Emmanuel Bourinet, Joël Bockaert, Philippe Marin, Franck Vandermoere

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The serotonin 5-HT2A and glutamate mGlu2 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-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A−/− mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalMolecular Psychiatry
DOIs
Publication statusAccepted/In press - Jun 1 2018

Fingerprint

Receptor, Serotonin, 5-HT2A
LY 379268
Phosphorylation
HEK293 Cells
Prefrontal Cortex
Antipsychotic Agents
Serotonin
LY 341495
Serotonin 5-HT2 Receptor Antagonists
Glutamate Receptors
G-Protein-Coupled Receptors
serine receptor
Alanine
Psychotic Disorders
Schizophrenia
Mutation
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling. / Murat, Samy; Bigot, Mathilde; Chapron, Jonathan; König, Gabriele M.; Kostenis, Evi; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bourinet, Emmanuel; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck.

In: Molecular Psychiatry, 01.06.2018, p. 1-17.

Research output: Contribution to journalArticle

Murat, Samy ; Bigot, Mathilde ; Chapron, Jonathan ; König, Gabriele M. ; Kostenis, Evi ; Battaglia, Giuseppe ; Nicoletti, Ferdinando ; Bourinet, Emmanuel ; Bockaert, Joël ; Marin, Philippe ; Vandermoere, Franck. / 5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling. In: Molecular Psychiatry. 2018 ; pp. 1-17.
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