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.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Duhr F,Déléris P,Raynaud F,Séveno M,Morisset-Lopez S,Mannoury la Cour C,Millan MJ,Bockaert J,Marin P,Chaumont-Dubel S

doi

10.1038/nchembio.1547

subject

Has Abstract

pub_date

2014-07-01 00:00:00

pages

590-7

issue

7

eissn

1552-4450

issn

1552-4469

pii

nchembio.1547

journal_volume

10

pub_type

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