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La phosphorylation du récepteur mGlu₂ du glutamate : mécanisme clé de son cross talk fonctionnel avec le récepteur 5-HT2A de la sérotonine

Abstract : The serotonin 5-HT2A and glutamate mGlu2 receptors keep on attracting particular attention given their implication in psychosis associated with schizophrenia and in the mechanism of action of atypical antipsychotics and of a new class of antipsychotics, respectively. Though atypical antipsychotics, targeting 5-HT2A receptor, are efficient against positive symptoms, these drugs do not act against negative, cognitive symptoms and display many side effects. Since the 90’s, new classes of antipsychotics triggering glutamatergic system, in particular mGlu2 receptor, have been developed. Their clinical trials have shown efficacy only in patients who have not been previously treated with atypical antipsychotics. This suggests a strong interaction between 5-HT2A and mGlu2 receptors in the mechanism of action of both classes of antipsychotics. Moreover, a large body of evidence indicates the presence, in prefontal cortex, of 5-HT2A/mGlu2 heteromer that is important for the response to hallucinogens and antipsychotics targeting one receptor or the other. Thus, in view of the importance of the phosphorylation profile adopted by G-protein coupled receptor (GPCR) on their activity, I characterized the impact of 5-HT2A receptor co-expression on the phosphorylation profile of mGlu2 receptor in response to various stimulations. Among the five identified phosphorylated residues, the phosphorylation of Ser843 increases upon mGlu2 receptor stimulation only when the 5-HT2A receptor is co-expressed. A new antibody against the phosphorylated form of Ser843 confirmed these results in HEK-293 cells and in mouse prefrontal cortex, area where both receptors are co-expressed. Functional studies demonstrated that Ser843 phosphorylation is necessary to enhance Gi/o signaling of mGlu2 receptor and constitutes a functional crosstalk between 5-HT2A and mGlu2 receptor since 5-HT2A receptor agonists also stimulate Ser843 phosphorylation. Collectively, my thesis findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event of the functional crosstalk with 5-HT2A receptor that might be critical to understand the mechanism of action of atypical and potential future antipsychotics treatments.
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Samy Murat. La phosphorylation du récepteur mGlu₂ du glutamate : mécanisme clé de son cross talk fonctionnel avec le récepteur 5-HT2A de la sérotonine. Sciences agricoles. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT002⟩. ⟨tel-01762633⟩

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