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Nat Chem Biol. 2014 Jul;10(7):590-7. doi: 10.1038/nchembio.1547. Epub 2014 Jun 1.

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

Author information

1
1] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Universités de Montpellier 1 and 2, UMR-5203, Montpellier, France.
2
UPR 4301 du CNRS, Centre de Biophysique Moléculaire, Orléans, France.
3
Institut de Recherches Servier, Croissy-sur-Seine, France.
4
1] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Universités de Montpellier 1 and 2, UMR-5203, Montpellier, France. [4].

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 Ca(2+) 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.

PMID:
24880860
DOI:
10.1038/nchembio.1547
[Indexed for MEDLINE]

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