ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors

Riccioni, Teresa; Bordi, Fabio; Minetti, Patrizia; Spadoni, Gilberto; Yun, Hyung Mun; Im, Bo Hye; Tarzia, Giorgio; Rhim, Hyewhon; Borsini, Franco

doi:10.1016/j.ejphar.2011.04.028

Cited by 24 publications

(23 citation statements)

References 21 publications

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“…To examine the role of 5-HT 6 R in osteoblast differentiation and function in vitro , primary osteoblasts were cultured and treated with a recently developed selective 5-HT 6 R agonist, ST193620. The activation effects of 5-HT 6 R were determined by ALP activity and the formation of mineralized bone nodules.…”

Section: Resultsmentioning

confidence: 99%

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

Yun

Park

Hong

et al. 2016

Sci Rep

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Serotonin is important in brain functions and involved in neurological diseases. It is also drawn considerable attention in bone disease since it mainly produced by the gut. Serotonin 6 G-protein-coupled receptor (5-HT6R) is clinical targets for the treatment of neurological diseases. However, 5-HT6R as a therapeutic target in bone has not been reported. Herein, we found that 5-HT6R showed higher expression in bone, and its expression was increased during bone remodeling and osteoblast differentiation. The activation of 5-HT6R by ST1936 caused the inhibition of ALP activity and mineralization in primary osteoblast cultures, which was antagonized by SB258585, an antagonist and by the knockdown of 5-HT6R. Further investigation indicated that 5-HT6R inhibited osteoblast differentiation via Jab1 in BMP2 signaling but not PKA and ERK1/2. In vivo studies showed that the activation of 5-HT6R inhibited bone regeneration in the calvarial defect mice and also delayed bone development in newborn mice; this response was antagonized by SB258585. Therefore, our findings indicate a key role of 5-HT6R in bone formation through serotonin originating in the peripheral system, and suggest that it is a novel therapeutic target for drug development in the bone repair and bone diseases.

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Section: Resultsmentioning

confidence: 99%

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

Yun

Park

Hong

et al. 2016

Sci Rep

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“…Thus, there are few 5-HT 6 R agonists, and only WAY-181187 (displays 50-fold selectivity against serotonergic and other receptors) has been characterized and widely used [46, 47]. Recently, a new 5-HT 6 R agonist, ST1936, has been reported and compared with the characteristics of WAY-181187 [48]. …”

Section: -Ht6r Agonists and Antagonistsmentioning

confidence: 99%

“…This is mainly due to the lack of pharmacological tools able to selectively activate 5-HT 6 Rs in the CNS. The selective 5-HT 6 R agonists have only recently been developed and characterized [47, 48, 65]. This lack of appropriate tools has also contributed to the inconsistent observations on the pharmacological and neurochemical effects of 5-HT 6 R antagonists.…”

Section: Neurochemical Mechanisms Of 5-ht6rsmentioning

confidence: 99%

The Serotonin-6 Receptor as a Novel Therapeutic Target

Yun

Rhim

2011

Exp Neurobiol

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Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors. Among them, the 5-HT6 receptor (5-HT6R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT6R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT6R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT6R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT6R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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receptors increases the likelihood for receptors to localize outside of the primary cilium and have been associated with changes in cilia morphology and dendritic outgrowth. In the present study, we explore the role of 5-HT6R rescue on neuronal morphology in primary neuronal cultures from 5-HT6R-KO mice, while maintaining a more physiological level of expression, wherein the receptor localizes to cilia in 80-90% of neurons (similar to endogenous 5-HT6R localization). We found that rescue of 5-HT6R expression is sufficient to increase cilia length and dendritic outgrowth, but primarily in neurons in which the receptor is located exclusively in the primary cilia. Additionally, we found that expression of 5-HT6R mutants, deficient in agonist-stimulated cAMP or without the predicted Fyn kinase binding domain, maintain constitutive activity for stimulating cAMP and still increased the length of cilia, while the proposed Fyn kinase domain was required for stimulating dendritic outgrowth. These findings highlight the complexity of 5-HT6R function and localization, particularly when using exogenous overexpression, and provide greater understanding and potential mechanisms for 5-HT6R drug therapies.

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ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors

Cited by 24 publications

References 21 publications

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

The Serotonin-6 Receptor as a Novel Therapeutic Target

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

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ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors

Cited by 24 publications

References 21 publications

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor

The Serotonin-6 Receptor as a Novel Therapeutic Target

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

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About

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