title: 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 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.
authors.affiliation: 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.
authors.forename: Fanny
authors.initials: F
authors.lastname: Duhr
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Déléris
authors.affiliation: 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.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: 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.
authors.forename: Martial
authors.initials: M
authors.lastname: Séveno
authors.affiliation: UPR 4301 du CNRS, Centre de Biophysique Moléculaire, Orléans, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Morisset-Lopez
authors.affiliation: Institut de Recherches Servier, Croissy-sur-Seine, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.affiliation: Institut de Recherches Servier, Croissy-sur-Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: 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.
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.affiliation: 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].
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.affiliation: 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].
authors.forename: Séverine
authors.initials: S
authors.lastname: Chaumont-Dubel
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; C418570:SB 258585; D013449:Sulfonamides; C097216:serotonin 6 receptor; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D020764:cdc42 GTP-Binding Protein