Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth

Abstract : The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5). Expression of 5-HT6Rs in NG108-15 cells induced neurite growth and expression of voltage-gated Ca2+ channels, two hallmarks of neuronal differentiation. 5-HT6R–elicited neurite growth was agonist independent and prevented by the 5-HT6R antagonist SB258585, which behaved as an inverse agonist. Moreover, it required receptor phosphorylation at Ser350 by Cdk5 and Cdc42 activity. Supporting a role of native 5-HT6Rs in neuronal differentiation, neurite growth of primary neurons was reduced by SB258585, by silencing 5-HT6R expression or by mutating Ser350 into alanine. These results reveal a functional interplay between Cdk5 and a G protein–coupled receptor to control neuronal differentiation.
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Fanny Duhr, Paul Déléris, Fabrice Raynaud, Martial Séveno, Séverine Morisset-Lopez, et al.. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nature Chemical Biology, Nature Publishing Group, 2014, 10 (7), pp.590-597. ⟨10.1038/nchembio.1547⟩. ⟨hal-01178901⟩



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