Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth
| Autor: | Fabrice Raynaud, Martial Séveno, Philippe Marin, Millan Mark, Séverine Morisset-Lopez, Paul Déléris, Séverine Chaumont-Dubel, Fanny Duhr, Joël Bockaert, Clotilde Mannoury la Cour |
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| Přispěvatelé: | Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Agonist
Calcium Channels L-Type medicine.drug_class [SDV]Life Sciences [q-bio] Primary Cell Culture CDC42 Molecular neuroscience Biology Ligands Hippocampus Piperazines Rats Sprague-Dawley Mice Cell Line Tumor Neurites medicine Animals Humans Gene silencing Inverse agonist Phosphorylation cdc42 GTP-Binding Protein Receptor Molecular Biology Sulfonamides Kinase Cyclin-dependent kinase 5 Gene Expression Regulation Developmental Cell Differentiation Cyclin-Dependent Kinase 5 Cell Biology Rats Cell biology nervous system Receptors Serotonin Mutation Signal Transduction |
| Zdroj: | Nature Chemical Biology Nature Chemical Biology, Nature Publishing Group, 2014, 10 (7), pp.590-597. ⟨10.1038/nchembio.1547⟩ |
| ISSN: | 1552-4450 1552-4469 |
| DOI: | 10.1038/nchembio.1547⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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