1. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth.
- Author
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Duhr, Fanny, Déléris, Paul, Raynaud, Fabrice, Séveno, Martial, Morisset-Lopez, Séverine, Mannoury la Cour, Clotilde, Millan, Mark J, Bockaert, Joël, Marin, Philippe, and Chaumont-Dubel, Séverine
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CYCLIN-dependent kinases , *SEROTONIN receptors , *NEURON development , *NEURODEVELOPMENTAL treatment , *G protein coupled receptors , *GENE silencing , *MUTAGENESIS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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