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.

SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling

“…Interestingly, hypoxia increases the expression level of 5-HT 6 R and Jab1, indicating that 5-HT 6 R and the Jab1 complex and its downstream signaling pathway protect the cells against hypoxia (Yun et al, 2010). A recent study has further shown that direct recruitment of CDK5 and p35 (also known as CDK5R1) to the C-terminus of 5-HT 6 R leads to the phosphorylation of this region and promotes neurite outgrowth by activating Cdc42 (Duhr et al, 2014). Such diverse 5-HT 6 R-mediated downstream signaling pathways and second messengers might explain why agonists and antagonists of 5-HT 6 R result in conflicting effects in different studies (Marazziti et al, 2011).…”

“…Besides Gas, 5-HT 6 R is known to interact with various proteins such as Fyn tyrosine kinase (Yun et al, 2007), Jun activation domain-binding protein-1 (Jab1, also known as COPS5) (Yun et al, 2010), mammalian target of rapamycin (mTOR) (Meffre et al, 2012), microtubule-associated protein 1B light chain (MAP1B-LC) (Kim et al, 2014) and cyclin-dependent kinase 5 (Cdk5) (Duhr et al, 2014). The C-terminus of 5-HT 6 R interacts with the Fyn and activation of 5-HT 6 R stimulates (B-D) HEK293T cells were co-transfected with HA-5-HT6R or HA-b2AR and EGFP-C1 or EGFP-RGSPX.…”

N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties

“…Furthermore, 5-HT 6 R activates mTOR Complex 1 (mTORC1) in the prefrontal cortex, which is related to cognitive deficits, 2 and the receptor constitutively activates Cdk5 to control cortical neurons migration and promote neurite growth. 3 Blockade of 5-HT 6 R enhances cognitive performance in a broad range of tasks in rodents, 4,5 and phase II clinical studies have demonstrated efficacy of 5-HT 6 R antagonists (Iladopirdine = LuAE58054, SB742457, and AVN-211, Figure 1) in conjunction with donepezil in mild-to-moderate AD patients.…”

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

“…As a G-protein coupled receptor, 5-HT6 is positively coupled with G-proteins that stimulate production of cAMP, presumably through adenylyl cyclase III (AC3), the only adenylyl cyclase known to localize only to primary neuronal cilia (Sebben et al, 1994;Kohen et al, 2001;Kang et al, 2005;Bishop et al, 2007;Domire and Mykytyn, 2009). More recently, proteomic analysis of 5-HT6R protein association has identified a variety of non-canonical signaling pathways, including CDK5, Fyn kinase, Jab1 and mTOR (Yun et al, 2010;Riccioni et al, 2011;Meffre et al, 2012;Duhr et al, 2014). 5-HT6R displays a high level of ligand-independent constitutive activity, and this was proposed to regulate cortical neuronal migration and morphology (Grimaldi et al, 1998;Romero et al, 2007;Jacobshagen, Niquille, and ChaumontDubel, 2014;Dayer et al, 2015).…”