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Optical control of sphingosine-1-phosphate formation and function.

ABSTRACT: Sphingosine-1-phosphate (S1P) plays important roles as a signaling lipid in a variety of physiological and pathophysiological processes. S1P signals via a family of G-protein-coupled receptors (GPCRs) (S1P1-5) and intracellular targets. Here, we report on photoswitchable analogs of S1P and its precursor sphingosine, respectively termed PhotoS1P and PhotoSph. PhotoS1P enables optical control of S1P1-3, shown through electrophysiology and Ca2+ mobilization assays. We evaluated PhotoS1P in vivo, where it reversibly controlled S1P3-dependent pain hypersensitivity in mice. The hypersensitivity induced by PhotoS1P is comparable to that induced by S1P. PhotoS1P is uniquely suited for the study of S1P biology in cultured cells and in vivo because it exhibits prolonged metabolic stability compared to the rapidly metabolized S1P. Using lipid mass spectrometry analysis, we constructed a metabolic map of PhotoS1P and PhotoSph. The formation of these photoswitchable lipids was found to be light dependent, providing a novel approach to optically probe sphingolipid biology.

SUBMITTER: Morstein J

PROVIDER: S-EPMC7428055 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Sphingosine 1-phosphate

Project description: Not available

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Sphingosine 1-phosphate induces filopodia formation through S1PR2 activation of ERM proteins.

Project description:Previously we demonstrated that the sphingolipids ceramide and S1P (sphingosine 1-phosphate) regulate phosphorylation of the ERM (ezrin/radixin/moesin) family of cytoskeletal proteins [Canals, Jenkins, Roddy, Hernande-Corbacho, Obeid and Hannun (2010) J. Biol. Chem. 285, 32476-3285]. In the present article, we show that exogenously applied or endogenously generated S1P (in a sphingosine kinase-dependent manner) results in significant increases in phosphorylation of ERM proteins as well as filopodia formation. Using phosphomimetic and non-phosphorylatable ezrin mutants, we show that the S1P-induced cytoskeletal protrusions are dependent on ERM phosphorylation. Employing various pharmacological S1PR (S1P receptor) agonists and antagonists, along with siRNA (small interfering RNA) techniques and genetic knockout approaches, we identify the S1PR2 as the specific and necessary receptor to induce phosphorylation of ERM proteins and subsequent filopodia formation. Taken together, the results demonstrate a novel mechanism by which S1P regulates cellular architecture that requires S1PR2 and subsequent phosphorylation of ERM proteins.

| S-EPMC3623934 | biostudies-literature

Interaction of microRNAs with sphingosine kinases, sphingosine-1 phosphate, and sphingosine-1 phosphate receptors in cancer.

Project description:Sphingosine-1-phosphate (S1P), a pleiotropic lipid mediator, participates in various cellular processes during tumorigenesis, including cell proliferation, survival, drug resistance, metastasis, and angiogenesis. S1P is formed by two sphingosine kinases (SphKs), SphK1 and SphK2. The intracellularly produced S1P is delivered to the extracellular space by ATP-binding cassette (ABC) transporters and spinster homolog 2 (SPNS2), where it binds to five transmembrane G protein-coupled receptors to mediate its oncogenic functions (S1PR1-S1PR5). MicroRNAs (miRNAs) are small non-coding RNAs, 21-25 nucleotides in length, that play numerous crucial roles in cancer, such as tumor initiation, progression, apoptosis, metastasis, and angiogenesis via binding to the 3'-untranslated region (3'-UTR) of the target mRNA. There is growing evidence that various miRNAs modulate tumorigenesis by regulating the expression of SphKs, and S1P receptors. We have reviewed various roles of miRNAs, SphKs, S1P, and S1P receptors (S1PRs) in malignancies and how notable miRNAs like miR-101, miR-125b, miR-128, and miR-506, miR-1246, miR-21, miR-126, miR499a, miR20a-5p, miR-140-5p, miR-224, miR-137, miR-183-5p, miR-194, miR181b, miR136, and miR-675-3p, modulate S1P signaling. These tumorigenesis modulating miRNAs are involved in different cancers including breast, gastric, hepatocellular carcinoma, prostate, colorectal, cervical, ovarian, and lung cancer via cell proliferation, invasion, angiogenesis, apoptosis, metastasis, immune evasion, chemoresistance, and chemosensitivity. Therefore, understanding the interaction of SphKs, S1P, and S1P receptors with miRNAs in human malignancies will lead to better insights for miRNA-based cancer therapy.

| S-EPMC8777508 | biostudies-literature

Extracellular sphingosine 1-phosphate stimulates formation of ethanolamine from phosphatidylethanolamine: modulation of sphingosine 1-phosphate-induced mitogenesis by ethanolamine.

Project description:In this work, we determined the effects of sphingosine 1-phosphate (S1P) on phospholipase D (PLD)-mediated hydrolysis of phosphatidylethanolamine (PtdEtn), and evaluated the effects of the water-soluble product ethanolamine on S1P-induced DNA synthesis in NIH 3T3 cells. In [14C]ethanolamine-labelled cells, S1P (0.5-5 microM) stimulated PLD-mediated hydrolysis of PtdEtn 1.5-2.1-fold. Down-regulation of protein kinase C by chronic (24 h) treatment of cells with 300 nM PMA, or pretreatments (10 min) with the cell-permeant calcium chelator 1,2-bis-(O-aminophenoxy)-ethane-N,N, N',N'-tetra-acetic acid tetra-acetoxymethyl ester led to the inhibition of S1P-induced PtdEtn hydrolysis. S1P alone was a weak inducer of DNA synthesis, but its effects were enhanced by phosphocholine (PCho), insulin, ATP or PMA. Ethanolamine (5-100 microM) did not modify the mitogenic effect of S1P alone, whereas at 50-100 microM concentrations it actually enhanced the mitogenic effect of PCho via a mitogen-activated protein (MAP) kinase-independent mechanism. In contrast, 5-20 microM concentrations of ethanolamine, which correspond to normal blood ethanolamine levels in humans, strongly inhibited DNA synthesis induced by S1P plus PCho via a MAP kinase-dependent mechanism; importantly, less or no inhibition was observed with 50-100 microM concentrations of ethanolamine. At 5-50 microM concentrations, ethanolamine also inhibited the synergistic mitogenic effects of both S1P plus insulin (22-27% inhibition) and PCho plus ATP (45-73% inhibition) but not those of S1P plus PMA or S1P plus ATP. The results indicate that S1P stimulates PLD-mediated hydrolysis of PtdEtn by a mechanism that may involve a regulatory protein kinase C isoform. Increased formation of ethanolamine by PLD-mediated PtdEtn hydrolysis or by other means may be required for maximal stimulation of DNA synthesis by S1P in the presence of insulin, and particularly PCho.

| S-EPMC1218932 | biostudies-other

The role of sphingosine-1-phosphate transporter Spns2 in immune system function.

Project description:Sphingosine-1-phosphate (S1P) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of S1P transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate S1P transport in cell culture. Spns2 was also shown to control S1P activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different S1P-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2(tm1a(KOMP)Wtsi) allele (Spns2(tm1a)). The Spns2(tm1a/tm1a) animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2(tm1a/tm1a) mice closely mimicked the phenotypes of partial S1P deficiency and impaired S1P-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2(tm1a/tm1a) resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the S1P signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard.

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Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Osteoclasts of wildtype and Calcr-/- C57Bl/6 mice were treated with Calcitonin and compared to the non-treated osteoclasts of wildtype or Calcr-/- mice, respectively.

2014-10-19 | E-GEOD-60761 | biostudies-arrayexpress

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

2014-10-19 | GSE60761 | GEO

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.

Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

| S-EPMC4205484 | biostudies-literature

Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease.

Project description:BACKGROUND: The accumulation of beta amyloid (A?) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, A? accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that A? peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. RESULTS: Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. CONCLUSIONS: Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

| S-EPMC3912487 | biostudies-literature

Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis.

Project description:Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.

| S-EPMC4899780 | biostudies-literature

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