Sphingosine‐1‐phosphate induces proliferation and morphological changes of neural progenitor cells

Harada, Jun; Foley, Melissa; Moskowitz, Michael A.; Waeber, Christian

doi:10.1046/j.1471-4159.2003.02219.x

Cited by 186 publications

(161 citation statements)

References 69 publications

(74 reference statements)

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“…Weiner et al (65) previously reported that LPA induced cell-cell junctions containing N-cadherin in rat Schwann cells. Furthermore, LPA was reported to induce cell clustering in neural progenitor cells prepared from embryonic rat hippocampus (66) and in mouse postmitotic cortical neurons (16). Our results raise the possibility that in addition to LPA 1 and LPA 2 , LPA 4 might also be involved in these effects in neural cells and have critical roles in the development and function of the nervous system.…”

Section: Discussionmentioning

confidence: 59%

LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

Yanagida

Ishii

Hamano

et al. 2007

Journal of Biological Chemistry

101

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Section: Discussionmentioning

confidence: 59%

LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

Yanagida

Ishii

Hamano

et al. 2007

Journal of Biological Chemistry

101

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“…[5,6] Although the precise regulation of these receptors by locally released S1P remains unclear, S1P receptors are thought to play a role in such events as astrocyte migration, [7] oligodendrocyte differentiation, and cell survival [8,9] and neurogenesis. [10,11] To assess the relevance of individual S1P receptor subtypes for the activity of FTY720-P, selective agonists are required. Because S1P5 receptors are expressed on oligodendrocytes, and S1P5 receptors are thought to play a role in oligodendrocyte differentiation and survival, we focused on the development of S1P5 agonists.…”

mentioning

confidence: 99%

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

et al. 2010

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The immunomodulatory drug fingolimod (FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), derived from a fungal metabolite myriocin), is phosphorylated in vivo by sphingosine kinases to produce (R)-FTY720-phosphate (FTY720-P). [1,2] FTY720-P activates sphingosine-1-phosphate (S1P) receptors S1P1, S1P3, S1P4, and S1P5 at low nanomolar concentrations and is inactive toward the S1P2 receptor.[1] The FTY720-P-mediated activation of the S1P1 receptor on lymphocytes induces receptor internalization, which attenuates T-cell response to S1P gradients, preventing their egress from secondary lymphoid tissues. [3] In addition to playing a role in the immune system, all S1P receptors except S1P4 are also found differentially expressed in the central nervous system [4] and on various tumor cell types. [5,6] Although the precise regulation of these receptors by locally released S1P remains unclear, S1P receptors are thought to play a role in such events as astrocyte migration, [7] oligodendrocyte differentiation, and cell survival [8,9] and neurogenesis. [10,11] To assess the relevance of individual S1P receptor subtypes for the activity of FTY720-P, selective agonists are required. Because S1P5 receptors are expressed on oligodendrocytes, and S1P5 receptors are thought to play a role in oligodendrocyte differentiation and survival, we focused on the development of S1P5 agonists. By using a highthroughput screening calcium mobilization assay with GPCR priming and FLIPR technology, [12] we discovered benzamide 1, which has good in vitro potency toward the S1P5 receptor (EC 50 = 270 nm), but has modest selectivity against S1P1 (EC 50 = 3140 nm) and S1P4 (EC 50 = 100 nm). Herein we report our studies of various benzamide modifications carried out to improve the selectivity, bioactivity, pharmacokinetic properties, and ancillary profile of 1, ultimately resulting in the discovery of potent and very selective S1P5 agonists.To guide the optimization process, homology models of all S1P receptors were built from a crystal structure of bovine rhodopsin (PDB ID: 1F88). [13] Docking experiments of 1 into these models revealed a possible location of the binding site, some essential features of the interactions, and indicated potential regions for gaining selectivity and improving potency. In these complexes (Figure 1), 1 adopts a twisted conformation with the aniline ring,~708 out of the benzamide plane and stabilized by a hydrogen bond between the aniline NH group and the amide carbonyl. In the S1P5 receptor complex, the amide group forms a hydrogen bond with OG1-Thr120. The benzamide phenyl ring lies in a large hydrophobic pocket surrounded by Phe196, Phe201, Phe268, Leu119, Trp264, Leu267, and Leu271. The aniline ring undergoes a T-shaped interaction with Phe116 and hydrophobic contacts with Leu271 and Leu292. The ortho-methyl substituents fill a small pocket formed by Tyr89, Val115, and Leu292 on one side, and sit at the face of Phe196 on the other side. Inspection of sequence alignments (Figure 2) revealed two positions, o...

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“…S1P 3 primarily localizes to the cell surface on the plasma membrane, and high expression levels of S1P 3 have been detected in lung, heart, kidney, spleen, diaphragm, and intestine tissues [65]. Moreover, for neurogenesis and for expression of smooth muscle alpha-actin following arterial injury [66], S1P 3 has been found to be essential [67]. S1P 3 also contributes to the migration of thyroid cancer cells [68] and VEGF-A secretion induced by S1P [69].…”

Section: S1p/s1pr Systemmentioning

confidence: 99%

Role of Smad3 and S1P Signaling in Mandibular Condylar Cartilage Homeostasis

Izawa¹,

Hutami²,

Mori³

et al. 2017

J Bone Res

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Osteoarthritis (OA), the most common degenerative joint disease, results from an imbalance between chondrocyte-controlled anabolic and catabolic processes. OA is characterized by progressive degradation of components of the Extracellular Matrix (ECM) within the articular cartilage, correlated with secondary inflammation. Several studies had investigated the morphological and biochemical changes during OA progression. However, a comprehensive study of the OA pathogenesis still remains to be elucidated to find the best therapy for OA. In this review, recent advances in our understanding of the mechanisms of action of Sphingosine 1-phosphate (S1P) and Smad3 independently and in relation to Temporomandibular Joint Osteoarthritis (TMJ-OA) will be discussed. S1P receptors are expressed on the cell surface and are internalized upon binding of the bioactive lipid, S1P, as part of the migratory response. Meanwhile, Smad3 is an intracellular signaling molecule that mediates signaling from transforming growth factor-β (TGF-β) and activin receptors. Crosstalk between the TGF-β/Smad3 and S1P/S1P 3 signaling pathways regulates cell motility and apoptosis in chondrocyte cells. Thus, Smad3/S1P 3 signaling in chondrocytes may be responsible for the development of TMJ-OA, and the potential for these proteins to represent targets for the treatment of TMJ-OA warrants further study.

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Sphingosine‐1‐phosphate induces proliferation and morphological changes of neural progenitor cells

Cited by 186 publications

References 69 publications

LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

Role of Smad3 and S1P Signaling in Mandibular Condylar Cartilage Homeostasis

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