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1
Sumida, Grant M., and W. Daniel Stamer. "S1P2 receptor regulation of sphingosine-1-phosphate effects on conventional outflow physiology." American Journal of Physiology-Cell Physiology 300, no. 5 (May 2011): C1164—C1171. http://dx.doi.org/10.1152/ajpcell.00437.2010.
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Elevated intraocular pressure is the main risk factor in primary open-angle glaucoma, involving an increased resistance to aqueous humor outflow in the juxtacanalicular region of the conventional outflow pathway which includes the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC). Previously, sphingosine-1-phosphate (S1P) was shown to decrease outflow facility in porcine and human eyes, thus increasing outflow resistance and intraocular pressure. Owing to S1P's known effect of increasing barrier function in endothelial cells and the robust expression of the S1P1 receptor on the inner wall of SC, we hypothesized that S1P1 receptor activation promotes junction formation and decreases outflow facility. The effects of subtype-specific S1P receptor compounds were tested in human and porcine whole-eye perfusions and human primary cultures of SC and TM cells to determine the receptor responsible for S1P effects on outflow resistance. The S1P1-specific agonist SEW2871 failed to both mimic S1P effects in paired human eye perfusions, as well as increase myosin light chain (MLC) phosphorylation in cell culture, a prominent outcome in S1P-treated SC and TM cells. In contrast, the S1P2 antagonist JTE-013, but not the S1P1 or S1P1,3 antagonists, blocked the S1P-promoted increase in MLC phosphorylation. Moreover, JTE-013 prevented S1P-induced decrease in outflow facility in perfused human eyes ( P < 0.05, n = 6 pairs). Similarly, porcine eyes perfused with JTE-013 + S1P did not differ from eyes with JTE-013 alone ( P = 0.53, n = 3). These results demonstrate that S1P2, and not S1P1 or S1P3, receptor activation increases conventional outflow resistance and is a potential target to regulate intraocular pressure.
2
Lukas, Susan, Lori Patnaude, Sokol Haxhinasto, Anthony Slavin, Melissa Hill-Drzewi, Josh Horan, and Louise Kelly Modis. "No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation." Journal of Biomolecular Screening 19, no. 3 (September 3, 2013): 407–16. http://dx.doi.org/10.1177/1087057113502234.
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Sphingosine-1-phosphate (S1P) is a bioactive metabolite with pleiotropic effects on multiple cellular processes in health and disease. Responses elicited by S1P are a result of binding to five specific G-protein–coupled receptors. We have developed multiple assays to systematically study the downstream signaling of these receptors, including early events such as direct receptor activation (GTPγS) as well as more distal events such as S1P1 receptor degradation. Employing such assays, we have characterized and compared multiple S1P1 agonists that are in clinical development including FTY720, BAF312, CS-0777, and other molecules from the S1P1 patent literature. Our parallel assessment has allowed us to compare their potency against S1P1, their selectivity against the four other S1P receptors, as well as species cross-reactivity. We note that all of the compounds studied signal in an identical manner through S1P1, leading to receptor degradation.
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Zhang, Dong Dong, Bona Linke, Jing Suo, Aleksandra Zivkovic, Yannick Schreiber, Nerea Ferreirós, Marina Henke, Gerd Geisslinger, Holger Stark, and Klaus Scholich. "Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors." Biological Chemistry 396, no. 6-7 (June 1, 2015): 783–94. http://dx.doi.org/10.1515/hsz-2014-0276.
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Abstract FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.
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Hafizi, Redona, Faik Imeri, Roland H. Wenger, and Andrea Huwiler. "S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization." International Journal of Molecular Sciences 22, no. 17 (August 31, 2021): 9467. http://dx.doi.org/10.3390/ijms22179467.
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Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.
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Werth, Stephan, Helge Müller-Fielitz, and Walter Raasch. "Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism." Journal of Endocrinology 235, no. 3 (December 2017): 251–65. http://dx.doi.org/10.1530/joe-16-0550.
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Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100–300 µg/kgbw) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely.
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Zhang, Gengqian, Sulei Xu, Yan Qian, and Pingnian He. "Sphingosine-1-phosphate prevents permeability increases via activation of endothelial sphingosine-1-phosphate receptor 1 in rat venules." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1494—H1504. http://dx.doi.org/10.1152/ajpheart.00462.2010.
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Sphingosine-1-phosphate (S1P) has been demonstrated to enhance endothelial barrier function in vivo and in vitro. However, different S1P receptor subtypes have been indicated to play different or even opposing roles in the regulation of vascular barrier function. This study aims to differentiate the roles of endogenous endothelial S1P subtype receptors in the regulation of permeability in intact microvessels using specific receptor agonist and antagonists. Microvessel permeability was measured with hydraulic conductivity ( Lp) in individually perfused rat mesenteric venules. S1P-mediated changes in endothelial intracellular Ca2+ concentration ([Ca2+]i) was measured in fura-2-loaded venules. Confocal images of fluorescent immunostaining illustrated the spatial expressions of three S1P subtype receptors (S1PR1–3) in rat venules. The application of S1P (1 μM) in the presence of S1PR1–3 inhibited platelet-activating factor- or bradykinin-induced permeability increase. This S1P effect was reversed only with a selective S1PR1 antagonist, W-146, and was not affected by S1PR2 or S1PR3 antagonists JTE-013 and CAY-10444, respectively. S1PR1 was also identified as the sole receptor responsible for S1P-mediated increases in endothelial [Ca2+]i. S1PR2 or S1PR3 antagonist alone affected neither basal Lp nor platelet-activating factor-induced permeability increase. The selective S1PR1 agonist, SEW-2871, showed similar [Ca2+]i and permeability effect to that of S1P. These results indicate that, despite the presence of S1PR1–3 in the intact venules, only the activation of endothelial S1PR1 is responsible for the protective action of S1P on microvessel permeability and that endogenous S1PR2 or S1PR3 did not exhibit functional roles in the regulation of permeability under basal or acutely stimulated conditions.
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Corvino, Angela, Ida Cerqua, Alessandra Lo Bianco, Giuseppe Caliendo, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli, et al. "Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis." International Journal of Molecular Sciences 22, no. 16 (August 17, 2021): 8861. http://dx.doi.org/10.3390/ijms22168861.
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S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.
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Toebbe, JT, and Mary Beth Genter. "An Update on Sphingosine-1-Phosphate and Lysophosphatidic Acid Receptor Transcripts in Rodent Olfactory Mucosa." International Journal of Molecular Sciences 23, no. 8 (April 14, 2022): 4343. http://dx.doi.org/10.3390/ijms23084343.
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Olfactory neurons connect the external environment and the brain, allowing the translocation of materials from the nasal cavity into the brain. The olfactory system is involved in SARS-CoV-2 infections; early in the pandemic declared in 2020, a loss of the sense of smell was found in many infected patients. Attention has also been focused on the role that the olfactory epithelium appears to play in the entry of the SARS-CoV-2 virus into the brain. Specifically, SARS-CoV-2 enters cells via the angiotensin-converting enzyme 2 protein (ACE2), which is found on supporting cells in the olfactory epithelium. The intranasal administration of sphingosine has been proposed to prevent the binding of SARS-CoV-2 to ACE2. Further, sphingosine-1-phosphate (S1P) receptors appear to facilitate the entry of SARS-CoV-2 into the brain. The goal of these studies was to characterize S1P receptor expression status in rodent olfactory mucosa. The expression of receptors for a related sphingolipid, lysophosphatidic acid (LPA), was also assessed. The results confirm previous reports of S1P1 and S1P3 receptor expression, as well as LPA receptor 1, in mouse olfactory mucosa; moreover, they extend the previous findings to identify additional S1P and LPA receptor transcripts in rat and mouse olfactory mucosa, as well as in cultured olfactory neurons. These findings may enhance the utility of rodent models in identifying agonists and/or antagonists of S1P and LPA receptors that may block the entry of SARS-CoV-2 and other viruses into nasal epithelial cells, and prevent transmission from the nasal cavity into the brain.
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Godessart, Nuria, Sanam Mustafa, Vlad Dolgachev, Mariona Aulí, Núria Aguilar, Judit Cabedo, Marta Calbet, et al. "The S1P1 receptor antagonist W146 induces lymphopenia in mice. Demonstration that functional antagonism of S1P1 is the mechanism of lymphopenia evoked by fingolimod-like compounds. (140.15)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 140.15. http://dx.doi.org/10.4049/jimmunol.184.supp.140.15.
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Abstract Agonists of sphingosine 1-phosphate receptor 1 (S1P1) are a novel class of immunosuppressants. S1P is the endogenous agonist of S1P1 and promotes lymphocyte egress from lymph nodes (LN) into blood. However, synthetic agonists like fingolimod prevent the egress, causing systemic lymphopenia. This apparent contradiction is explained by the concept of functional antagonism, according to which synthetic S1P1 agonists induce receptor internalization, making cells unresponsive to the endogenous S1P. If this mechanism is true, S1P1 antagonists should induce lymphopenia. We have fully characterized compound W146, a S1P1 antagonist, by binding and cellular assays. We then administered W146 and several S1P1 agonists to mice and measured blood lymphocytes and plasma levels of compounds in different experimental conditions. All compounds induced lymphopenia in blood and a concomitant increase of CD4+ and CD8+ T cells in LN. These results indicated that lymphopenia evoked by W146 was due to S1P1 blockade and not to another mechanism, like cytotoxicity. By Western blot, FACS and immunocytochemistry we showed that all compounds but W146 induce S1P1 internalization. W146 is able to prevent the internalization induced by an agonist. We report, for the first time, lymphopenia with a S1P1 antagonist. Plasma levels needed to surmount the effects of endogenous S1P are achieved in our experimental conditions. Our studies strongly support the validity of the concept of functional antagonism.
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Juarez, Julius G., Nadia Harun, Marilyn Thien, Robert Welschinger, Rana Baraz, Aileen Dela Pena, Stuart M. Pitson, et al. "Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice." Blood 119, no. 3 (January 19, 2012): 707–16. http://dx.doi.org/10.1182/blood-2011-04-348904.
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Abstract CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P1) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P1 are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P1 agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P1 agonist may prove to be sufficient for mobilizing HSCs in normal donors for transplantation purposes, potentially providing a single mobilization procedure and eliminating the need to expose normal donors to G-CSF with its associated side effects.
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Seitz, Gabriele, Sedat Yildirim, Andreas M. Boehmler, Lothar Kanz, and Robert Möhle. "Sphingosine 1-Phosphate (S1P) Induces Migration and ERK/MAP-Kinase-Dependent Proliferation in Chronic Lymphocytic Leukemia (B-CLL) Due to Expression of the G Protein-Coupled Receptors S1P1/4." Blood 106, no. 11 (November 16, 2005): 4996. http://dx.doi.org/10.1182/blood.v106.11.4996.4996.
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Abstract Egress of lymphocytes from lymphoid organs into the circulation has been shown to depend on the presence of the lipid mediator sphingosine 1-phosphate (S1P) in the peripheral blood, and expression of corresponding S1P receptors (i.e., S1P1), that belong to the family of 7-transmembrane G protein-coupled receptors (GPCR). As circulating lymphocytic lymphoma cells are a hallmark of chronic lymphocytic leukemia, we analyzed expression of different S1P receptors and the effects of S1P on B-CLL cells. By qualitative and quantitative (TaqMan) RT-PCR, significant mRNA expression of S1P1 and S1P4 was found in CLL cell lines (EHEB, MEC-1) and in most samples (S1P1 in 88%, S1P4 in 100%) of primary CD19+ cells isolated from the peripheral blood of untreated B-CLL patients. mRNA of other S1P receptors (S1P2, S1P3, S1P5) was less consistently detected. Normal, nonmalignant B cells were strongly positive for S1P1, while other S1P receptors were weakly expressed or negative. S1P induced typical effects of chemotactic GPCR, such as actin polymerization (analyzed by flow cytometry) and chemotaxis (measured in a modified Boyden chamber assay) in CLL cell lines and primary B-CLL cells. After serum deprivation in vitro, S1P induced phosphorylation of ERK/MAP-kinase as analyzed by Western blot, demonstrating that S1P receptors expressed in CLL were able to activate signaling pathways of GPCR not only related to cell migration and chemotaxis, but also to cell proliferation. Of note, the S1P1 ligand FTY720, which induces receptor internalization after prolonged exposure and acts as an antagonist, resulted in apoptosis in CLL cell lines and primary CLL cells in vitro, as measured by MTT-test and staining with Annexin-FITC, respectively. We conclude that sphingosine 1-phosphate, which is present in the peripheral blood in considerable amounts, contributes to the trafficking of B-CLL cells expressing the GPCRs S1P1/4, and to their prolonged survival.
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Kitada, Yoshihiko, Kazuo Kajita, Koichiro Taguchi, Ichiro Mori, Masahiro Yamauchi, Takahide Ikeda, Mikako Kawashima, et al. "Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet-Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice." Endocrinology 157, no. 5 (March 4, 2016): 1839–51. http://dx.doi.org/10.1210/en.2015-1768.
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Abstract Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic β-cells. Among its 5 cognate receptors (S1pr1–S1pr5), S1P seems to counteract insulin signaling and confer insulin resistance via S1pr2 in these cells. S1P may also regulate insulin resistance in adipocytes, but the S1pr subtype(s) involved remains unknown. Here, we investigated systemic glucose/insulin tolerance and phenotypes of epididymal adipocytes in high-fat diet (HFD)-fed wild-type and S1pr2-deficient (S1pr2−/−) mice. Adult S1pr2−/− mice displayed smaller body/epididymal fat tissue weights, but the differences became negligible after 4 weeks with HFD. However, HFD-fed S1pr2−/− mice displayed better scores in glucose/insulin tolerance tests and had smaller epididymal adipocytes that expressed higher levels of proliferating cell nuclear antigen than wild-type mice. Next, proliferation/differentiation of 3T3-L1 and 3T3-F442A preadipocytes were examined in the presence of various S1pr antagonists: JTE-013 (S1pr2 antagonist), VPC-23019 (S1pr1/S1pr3 antagonist), and CYM-50358 (S1pr4 antagonist). S1P or JTE-013 treatment of 3T3-L1 preadipocytes potently activated their proliferation and Erk phosphorylation, whereas VPC-23019 inhibited both of these processes, and CYM-50358 had no effects. In contrast, S1P or JTE-013 treatment inhibited adipogenic differentiation of 3T3-F442A preadipocytes, whereas VPC-23019 activated it. The small interfering RNA knockdown of S1pr2 promoted proliferation and inhibited differentiation of 3T3-F442A preadipocytes, whereas that of S1pr1 acted oppositely. Moreover, oral JTE-013 administration improved glucose tolerance/insulin sensitivity in ob/ob mice. Taken together, S1pr2 blockade induced proliferation but suppressed differentiation of (pre)adipocytes both in vivo and in vitro, highlighting a novel therapeutic approach for obesity/type 2 diabetes.
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Gandy, K. Alexa Orr, Daniel Canals, Mohamad Adada, Masayuki Wada, Patrick Roddy, Ashley J. Snider, Yusuf A. Hannun, and Lina M. Obeid. "Sphingosine 1-phosphate induces filopodia formation through S1PR2 activation of ERM proteins." Biochemical Journal 449, no. 3 (January 9, 2013): 661–72. http://dx.doi.org/10.1042/bj20120213.
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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.
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Zhu, Qing, Min Xia, Zhengchao Wang, Pin-Lan Li, and Ningjun Li. "A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate." American Journal of Physiology-Renal Physiology 301, no. 1 (July 2011): F35—F41. http://dx.doi.org/10.1152/ajprenal.00014.2011.
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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine. S1P has been indicated to play a significant role in the cardiovascular system. It has been shown that the enzymes for S1P metabolism are expressed in the kidneys. The present study characterized the expression of S1P receptors in the kidneys and determined the role of S1P in the control of renal hemodynamics and sodium excretion. Real-time RT-PCR analyses showed that S1P receptors S1P1, S1P2, and S1P3 were most abundantly expressed in the renal medulla. Immunohistochemistry revealed that all three types of S1P receptors were mainly located in collecting ducts. Intramedullary infusion of FTY720, an S1P agonist, produced a dramatic increase in sodium excretion by twofold and a small but significant increase in medullary blood flow (16%). Administration of W146, an S1P1 antagonist, into the renal medulla blocked the effect of FTY720 and decreased the sodium excretion by 37% when infused alone. The antagonists of S1P2 and S1P3 had no effect. FTY720 produced additive natriuretic effects in combination with different sodium transporter inhibitors except amiloride, an epithelial sodium channel blocker. In the presence of nitric oxide synthase inhibitor l-NAME, FTY720 still increased sodium excretion. These data suggest that S1P produces natriuretic effects via activation of S1P1 in the renal medulla and this natriuretic effect may be through inhibition of epithelial sodium channel, which is nitric oxide independent. It is concluded that S1P is a novel diuretic factor in the renal medulla and may be an important regulator of sodium homeostasis.
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Chumanevich, Alena, Piper Wedman, and Carole A. Oskeritzian. "Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2." Mediators of Inflammation 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/1503206.
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Mast cells (MC) are present in most vascularized tissues around the vasculature likely exerting immunomodulatory functions. Endowed with diverse mediators, resident MC represent first-line fine-tuners of local microenvironment. Sphingosine-1-phosphate (S1P) functions as a pluripotent signaling sphingolipid metabolite in health and disease. S1P formation occurs at low levels in resting MC and is upregulated upon activation. Its export can result in type 2 S1P receptor- (S1PR2-) mediated stimulation of MC, further fueling inflammation. However, the role of S1PR2 ligation in proangiogenic vascular endothelial growth factor- (VEGF-) A and matrix metalloproteinase- (MMP-) 2 release from MC is unknown. Using a preclinical MC-dependent model of acute allergic responses andin vitrostimulated primary mouse bone marrow-derived MC (BMMC) or human primary skin MC, we report that S1P signaling resulted in substantial amount of VEGF-A release. Similar experiments usingS1pr2-deficient mice or BMMC or selective S1P receptor agonists or antagonists demonstrated that S1P/S1PR2 ligation on MC is important for VEGF-A secretion. Further, we show that S1P stimulation triggered transcriptional upregulation of VEGF-A and MMP-2 mRNA in human but not in mouse MC. S1P exposure also triggered MMP-2 secretion from human MC. These studies identify a novel proangiogenic axis encompassing MC/S1P/S1PR2 likely relevant to inflammation.
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Balthasar, Sonja, Johanna Samulin, Hanna Ahlgren, Nina Bergelin, Mathias Lundqvist, Emil C. Toescu, Margaret C. Eggo, and Kid Törnquist. "Sphingosine 1-phosphate receptor expression profile and regulation of migration in human thyroid cancer cells." Biochemical Journal 398, no. 3 (August 29, 2006): 547–56. http://dx.doi.org/10.1042/bj20060299.
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S1P (sphingosine 1-phosphate) receptor expression and the effects of S1P on migration were studied in one papillary (NPA), two follicular (ML-1, WRO) and two anaplastic (FRO, ARO) thyroid cancer cell lines, as well as in human thyroid cells in primary culture. Additionally, the effects of S1P on proliferation, adhesion and calcium signalling were addressed in ML-1 and FRO cells. All cell types expressed multiple S1P receptors. S1P evoked intracellular calcium signalling in primary cultures, ML-1 cells and FRO cells. Neither proliferation nor migration was affected in primary cultures, whereas S1P partly inhibited proliferation in ML-1 and FRO cells. Low nanomolar concentrations of S1P inhibited migration in FRO, WRO and ARO cells, but stimulated ML-1 cell migration. Consistently, S1P1 and S1P3, which mediate migratory responses, were strongly expressed in ML-1 cells, and S1P2, which inhibits migration, was the dominating receptor in the other cell lines. The migratory effect in ML-1 cells was mediated by Gi and phosphatidylinositol 3-kinase. Both S1P and the S1P1-specific agonist SEW-2871 induced Akt phosphorylation at Ser473. However, SEW-2871 failed to stimulate migration, whereas the S1P1/S1P3 antagonist VPC 23019 inhibited S1P-induced migration. The results suggest that aberrant S1P receptor expression may enhance thyroid cancer cell migration and thus contribute to the metastatic behaviour of some thyroid tumours.
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Niedernberg, Anke, Sorin Tunaru, Andree Blaukat, Bruce Harris, and Evi Kostenis. "Comparative Analysis of Functional Assays for Characterization of Agonist Ligands at G Protein-Coupled Receptors." Journal of Biomolecular Screening 8, no. 5 (October 2003): 500–510. http://dx.doi.org/10.1177/1087057103257555.
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A variety of functional assays are available for agonist or antagonist screening of G protein-coupled receptors (GPCRs), but it is a priori not predictable which assay is the most suitable to identify agonists or antagonists of GPCRs with therapeutic value in humans. More specifically, it is not known how a given set of GPCR agonists compares in different functional assays with respect to potency and efficacy and whether the level of the signaling cascade that is analyzed has any impact on the detection of agonistic responses. To address this question, the authors used the recently cloned human S1P5 receptor as a model and compared a set of 3 lipid ligands (sphingosine 1-phosphate [S1P], dihydro sphingosine 1-phosphate [dhS1P], and sphingosine) in 5 different functional assays: GTPγS binding, inhibition of adenylyl cyclase activity, mobilization of intracellular Ca2+ via the FLIPR and aequorin technology, and MAP kinase (ERK1/2) activation. S1P induced agonistic responses in all except the ERK1/2 assays with EC50 values varying by a factor of 10. Whereas dhS1P was identified as a partial agonist in the GTPγS assay, it behaved as a full agonist in all other settings. Sphingosine displayed partial agonistic activity exclusively in GTPγS binding assays. The findings suggest that assays in a given cellular background may vary significantly with respect to suitability for agonist finding and that ligands producing a response may not readily be detectable in all agonist assays. ( Journal of Biomolecular Screening 2003:500-510)
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Standoli, Sara, Sara Pecchioli, Daniel Tortolani, Camilla Di Meo, Federico Fanti, Manuel Sergi, Marina Bacci, et al. "The TRPV1 Receptor Is Up-Regulated by Sphingosine 1-Phosphate and Is Implicated in the Anandamide-Dependent Regulation of Mitochondrial Activity in C2C12 Myoblasts." International Journal of Molecular Sciences 23, no. 19 (September 21, 2022): 11103. http://dx.doi.org/10.3390/ijms231911103.
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The sphingosine 1-phosphate (S1P) and endocannabinoid (ECS) systems comprehend bioactive lipids widely involved in the regulation of similar biological processes. Interactions between S1P and ECS have not been so far investigated in skeletal muscle, where both systems are active. Here, we used murine C2C12 myoblasts to investigate the effects of S1P on ECS elements by qRT-PCR, Western blotting and UHPLC-MS. In addition, the modulation of the mitochondrial membrane potential (ΔΨm), by JC-1 and Mitotracker Red CMX-Ros fluorescent dyes, as well as levels of protein controlling mitochondrial function, along with the oxygen consumption were assessed, by Western blotting and respirometry, respectively, after cell treatment with methanandamide (mAEA) and in the presence of S1P or antagonists to endocannabinoid-binding receptors. S1P induced a significant increase in TRPV1 expression both at mRNA and protein level, while it reduced the protein content of CB2. A dose-dependent effect of mAEA on ΔΨm, mediated by TRPV1, was evidenced; in particular, low doses were responsible for increased ΔΨm, whereas a high dose negatively modulated ΔΨm and cell survival. Moreover, mAEA-induced hyperpolarization was counteracted by S1P. These findings open new dimension to S1P and endocannabinoids cross-talk in skeletal muscle, identifying TRPV1 as a pivotal target.
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Del Gaudio, Ilaria, Sebastian Hendrix, Christina Christoffersen, and Christian Wadsack. "Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis." International Journal of Molecular Sciences 21, no. 3 (January 25, 2020): 789. http://dx.doi.org/10.3390/ijms21030789.
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Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a powerful anti-inflammatory complex. This study aimed to elucidate the role of cord blood-derived HDL (nHDL) in feto-placental endothelial dysfunction. Here, we report that the exposure of primary fetal placental arterial endothelial cell (fPAEC) to healthy nHDL-S1P attenuated the ability of TNFα to activate NF-κB signaling and increase the expression of pro-inflammatory markers. Moreover, the angiotensin II (AngII)-induced reactive oxygen species (ROS) production was blunted in the presence of nHDL, whereas it was preserved when the cells were preincubated with S1P receptor antagonists, suggesting that S1P accounts for the vascular protective function of nHDL at the feto-placental unit. These results highlight the importance of HDL and S1P metabolism and signaling in pregnancy pathophysiology.
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Chen, Zhoumou, Timothy M. Doyle, Livio Luongo, Tally M. Largent-Milnes, Luigino Antonio Giancotti, Grant Kolar, Silvia Squillace, et al. "Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain." Proceedings of the National Academy of Sciences 116, no. 21 (May 8, 2019): 10557–62. http://dx.doi.org/10.1073/pnas.1820466116.
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Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.
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Tao, Rong, Holly E. Hoover, Norman Honbo, Mikaila Kalinowski, Conrad C. Alano, Joel S. Karliner, and Robert Raffai. "High-density lipoprotein determines adult mouse cardiomyocyte fate after hypoxia-reoxygenation through lipoprotein-associated sphingosine 1-phosphate." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 3 (March 2010): H1022—H1028. http://dx.doi.org/10.1152/ajpheart.00902.2009.
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The lipid mediator sphingosine 1-phosphate (S1P) confers survival benefits in cardiomyocytes and isolated hearts subjected to oxidative stress. High-density lipoprotein (HDL) is a major carrier of S1P in the serum, but whether HDL-associated S1P directly mediates survival in a preparation composed exclusively of cardiomyocytes has not been demonstrated. Accordingly, we tested the hypothesis that signal activation and survival during simulated ischemia-reperfusion injury in response to HDL require lipoprotein-associated S1P. As a model, we used adult mouse cardiomyocytes subjected to hypoxia-reoxygenation. Cells were treated or not with autologous mouse HDL, which significantly increased myocyte viability as measured by trypan blue exclusion. This survival effect was abrogated by the S1P1 and SIP3 receptor antagonist VPC 23019. The selective S1P3 antagonist CAY10444, the Gi antagonist pertussis toxin, the MEK (MAPK/ERK) kinase inhibitor PD-98059, and the phosphoinositide-3 kinase inhibitor wortmannin also inhibited the prosurvival effect of HDL. We observed that HDL activated both Akt (protein kinase B) and the MEK1/2-ERK1/2 pathway and also stimulated phosphorylation of glycogen synthase kinase-3β. ERK1/2 activation was through an S1P1 subtype receptor-Gi protein-dependent pathway, whereas the activation of Akt was inhibited by CAY10444, indicating mediation by S1P3 subtype receptors. We conclude that HDL, via its cargo of S1P, can directly protect cardiomyocytes against simulated oxidative injury in the absence of vascular effects and that prosurvival signal activation is dependent on both S1P1 and S1P3 subtype receptors.
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Latif, Ahmed Abdel, Anush K. Karapetyan, Yuri Klyachkin, Manjula Sunkara, Susan Smyth, Mariusz Z. Ratajczak, and Andrew J. Morris. "Novel Role for Bioactive Lipids in Mobilization of Bone Marrow Stem Cells During Myocardial Ischemia: Sphingosine-1 Phosphate (S1P) As Potential Therapeutic Target." Blood 120, no. 21 (November 16, 2012): 1911. http://dx.doi.org/10.1182/blood.v120.21.1911.1911.
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Abstract Abstract 1911 Background: Bone marrow (BM) contains a variety of stem cells, including mobile pool of hematopoietic stem cells and non-hematopoietic stem cells and acute myocardial infarction (AMI) triggers mobilization of BM-derived stem cells (BMSCs) through poorly understood processes. Recently we have postulated a major role for bioactive lipids such as sphingosine-1 phosphate (S1P) in G-CSF- and AMD3100-induced mobilization of hematopoietic stem cells (HSCs) into peripheral blood (PB) (Leukemia 2010;24:976–85). Hypothesis: We hypothesized that S1P could also play a role in mobilization of BMSCs in patients during tissue and organ injury as seen for example in patients with AMI. Methods: Peripheral blood (PB) samples from matched controls and patients presenting with ST-elevation myocardial infarction (STEMI) were examined i) by employing FACS for a number of circulating in PB lineage negative (Lin-)/CD45-/CD34+ and CD133+ and CXCR4+ BMSCs, ii) PB level of S1P by employing mass spectrometry, iii) SDF-1 level by ELISA and finally iv) BMSCs were tested in Transwell migration assays for their chemotactic responsiveness to S1P gradient in plasma from STEMI patients. Results: Plasma S1P levels were highest within 6 hours of AMI presentation 0.31 ± 0.02 μM and declined to 0.14 ± 0.02 μM in controls (P < 0.05 for 6 hours vs. controls). The elevation of plasma S1P corresponded with complement cascade (CC) activation and higher levels of C5b-C9 membrane attack complex (MAC) complex in the plasma. The largest reservoir of S1P in whole blood was red blood cells (RBCs) and incubation of RBCs with activated complement initiated the release of S1P. Elevated plasma S1P levels was paralleled by early significant increase in circulating lineage negative (Lin-)/CD45-/CD34+, CD133+ and CXCR4+ BMSCs (P < 0.01 vs. controls). Plasma obtained from STEMI patients in the early phases following acute injury stimulated the migration of human BM-derived Lin-/CXCR4+ and Lin-/CD34+ BMSCs in chemotaxis assays (7–8-fold increase vs. vehicle, P < 0.05), this effect was blunted by charcoal stripping of the plasma (CSP) and was further inhibited by the specific S1P receptor type 1 (S1P1) antagonists W146 (10 μM) and VPC20139 (10 μM). At the same time to our surprise we did not observed significant chemotactic relevant changes in SDF-1 level in PB plasma. Conclusion: This is the first human study to suggest that elevated S1P level in PB early in the course of AMI mobilizes BMSCs. Furthermore, we demonstrate for the first time that the release of hematopoietic and non-hematopoietic BMSCs into PB correlates in AMI patients with activation of CC and generation of MAC, that may release S1P from erythrocytes and platelets. We postulate that based on these results future studies examining the therapeutic manipulation of S1P and its receptors for myocardial regeneration are warranted. Disclosures: No relevant conflicts of interest to declare.
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Schira-Heinen, Jessica, Luzhou Wang, Seda Akgün, Sofia Blum, Brigida Ziegler, André Heinen, Hans-Peter Hartung, and Patrick Küry. "Modulation of Specific Sphingosine-1-Phosphate Receptors Augments a Repair Mediating Schwann Cell Phenotype." International Journal of Molecular Sciences 23, no. 18 (September 7, 2022): 10311. http://dx.doi.org/10.3390/ijms231810311.
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Transdifferentiation of Schwann cells is essential for functional peripheral nerve regeneration after injury. By activating a repair program, Schwann cells promote functional axonal regeneration and remyelination. However, chronic denervation, aging, metabolic diseases, or chronic inflammatory processes reduce the transdifferentiation capacity and thus diminish peripheral nerve repair. It was recently described that the sphingosine-1-phosphate receptor (S1PR) agonist Fingolimod enhances the Schwann cell repair phenotype by activation of dedifferentiation markers and concomitant release of trophic factors resulting in enhanced neurite growth. Since Fingolimod targets four out of five S1PRs (S1P1, S1P3-5) possibly leading to non-specific adverse effects, identification of the main receptor(s) responsible for the observed phenotypic changes is mandatory for future specific treatment approaches. Our experiments revealed that S1P3 dominates and that along with S1P1 acts as the responsible receptor for Schwann cell transdifferentiation as revealed by the combinatory application of specific agonists and antagonists. Targeting both receptors reduced the expression of myelin-associated genes, increased PDGF-BB representing enhanced trophic factor expression likely to result from c-Jun induction. Furthermore, we demonstrated that S1P4 and S1P5 play only a minor role in the adaptation of the repair phenotype. In conclusion, modulation of S1P1 and S1P3 could be effective to enhance the Schwann cell repair phenotype and thus stimulate proper nerve repair.
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Stockstill, Katherine, Timothy M. Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W. Little, Kathryn Braden, et al. "Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain." Journal of Experimental Medicine 215, no. 5 (April 27, 2018): 1301–13. http://dx.doi.org/10.1084/jem.20170584.
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The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.
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Landeen, Lee K., Dorothy A. Dederko, Colleen S. Kondo, Betty S. Hu, Nakon Aroonsakool, Jason H. Haga, and Wayne R. Giles. "Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 2 (February 2008): H736—H749. http://dx.doi.org/10.1152/ajpheart.00316.2007.
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Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K+ current ( IKACh) in the atrium that shortens action potential duration (APD) in the atrium. We have investigated probable mechanisms and receptor-subtype specificity for S1P-induced negative inotropy in isolated adult mouse ventricular myocytes. Activation of S1P receptors by S1P (100 nM) reduced cell shortening by ∼25% (vs. untreated controls) in field-stimulated myocytes. S1P1 was shown to be involved by using the S1P1-selective agonist SEW2871 on myocytes isolated from S1P3-null mice. However, in these myocytes, S1P3 can modulate a somewhat similar negative inotropy, as judged by the effects of the S1P1 antagonist VPC23019 . Since S1P1 activates Gi exclusively, whereas S1P3 activates both Gi and Gq, these results strongly implicate the involvement of mainly Gi. Additional experiments using the IKACh blocker tertiapin demonstrated that IKACh can contribute to the negative inotropy following S1P activation of S1P1 (perhaps through Giβγ subunits). Mathematical modeling of the effects of S1P on APD in the mouse ventricle suggests that shortening of APD (e.g., as induced by IKACh) can reduce L-type calcium current and thus can decrease the intracellular Ca2+ concentration ([Ca2+]i) transient. Both effects can contribute to the observed negative inotropic effects of S1P. In summary, these findings suggest that the negative inotropy observed in S1P-treated adult mouse ventricular myocytes may consist of two distinctive components: 1) one pathway that acts via Gi to reduce L-type calcium channel current, blunt calcium-induced calcium release, and decrease [Ca2+]i; and 2) a second pathway that acts via Gi to activate IKACh and reduce APD. This decrease in APD is expected to decrease Ca2+ influx and reduce [Ca2+]i and myocyte contractility.
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Stepanovska Tanturovska, Bisera, Aleksandra Zivkovic, Faik Imeri, Thomas Homann, Burkhard Kleuser, Holger Stark, and Andrea Huwiler. "ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo." Molecules 26, no. 17 (August 24, 2021): 5134. http://dx.doi.org/10.3390/molecules26175134.
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Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.
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Hla, Timothy, Sylvain Galvani, Shahin Rafii, and Ralph Nachman. "S1P and the birth of platelets." Journal of Experimental Medicine 209, no. 12 (November 19, 2012): 2137–40. http://dx.doi.org/10.1084/jem.20122284.
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Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P1 receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P1 receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12–CXCR4 axis. Pharmacologic modulation of the S1P1 receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P4 receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P1 duet that could potentially be harnessed for clinical translation.
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Maceyka, Michael, Sergio E. Alvarez, Sheldon Milstien, and Sarah Spiegel. "Filamin A Links Sphingosine Kinase 1 and Sphingosine-1-Phosphate Receptor 1 at Lamellipodia To Orchestrate Cell Migration." Molecular and Cellular Biology 28, no. 18 (July 21, 2008): 5687–97. http://dx.doi.org/10.1128/mcb.00465-08.
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ABSTRACT Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to produce the potent lipid mediator sphingosine-1-phosphate (S1P), which plays a critical role in cell motility via its cell surface receptors. Here, we have identified filamin A (FLNa), an actin-cross-linking protein involved in cell movement, as a bona fide SphK1-interacting protein. Heregulin stimulated SphK1 activity only in FLNa-expressing A7 melanoma cells but not in FLNa-deficient cells and induced its translocation and colocalization with FLNa at lamellipodia. SphK1 was required for heregulin-induced migration, lamellipodia formation, activation of PAK1, and subsequent FLNa phosphorylation. S1P directly stimulated PAK1 kinase, suggesting that it may be a target of intracellularly generated S1P. Heregulin also induced colocalization of S1P1 (promotility S1P receptor) but not S1P2, with SphK1 and FLNa at membrane ruffles. Moreover, an S1P1 antagonist inhibited the lamellipodia formation induced by heregulin. Hence, FLNa links SphK1 and S1P1 to locally influence the dynamics of actin cytoskeletal structures by orchestrating the concerted actions of the triumvirate of SphK1, FLNa, and PAK1, each of which requires and/or regulates the actions of the others, at lamellipodia to promote cell movement.
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Luo, Dongdong, Zhikun Guo, Xuecui Zhao, Lijuan Wu, Xiaochun Liu, Yingzhi Zhang, Yuhang Zhang, et al. "Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists." European Journal of Medicinal Chemistry 227 (January 2022): 113923. http://dx.doi.org/10.1016/j.ejmech.2021.113923.
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Lee, Chi-Ho, and Ji Woong Choi. "S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide." Antioxidants 10, no. 11 (October 27, 2021): 1706. http://dx.doi.org/10.3390/antiox10111706.
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The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.
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Lee, Jen-Fu, Sharon Gordon, Rosendo Estrada, Lichun Wang, Deanna L. Siow, Binks W. Wattenberg, David Lominadze, and Menq-Jer Lee. "Balance of S1P1and S1P2signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 1 (January 2009): H33—H42. http://dx.doi.org/10.1152/ajpheart.00097.2008.
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Sphingosine-1-phosphate (S1P) regulates various molecular and cellular events in cultured endothelial cells, such as cytoskeletal restructuring, cell-extracellular matrix interactions, and intercellular junction interactions. We utilized the venular leakage model of the cremaster muscle vascular bed in Sprague-Dawley rats to investigate the role of S1P signaling in regulation of microvascular permeability. S1P signaling is mediated by the S1P family of G protein-coupled receptors (S1P1-5receptors). S1P1and S1P2receptors, which transduce stimulatory and inhibitory signaling, respectively, are expressed in the endothelium of the cremaster muscle vasculature. S1P administration alone via the carotid artery was unable to protect against histamine-induced venular leakage of the cremaster muscle vascular bed in Sprague-Dawley rats. However, activation of S1P1-mediated signaling by SEW2871 and FTY720, two agonists of S1P1, significantly inhibited histamine-induced microvascular leakage. Treatment with VPC 23019 to antagonize S1P1-regulated signaling greatly potentiated histamine-induced venular leakage. After inhibition of S1P2signaling by JTE-013, a specific antagonist of S1P2, S1P was able to protect microvascular permeability in vivo. Moreover, endothelial tight junctions and barrier function were regulated by S1P1- and S1P2-mediated signaling in a concerted manner in cultured endothelial cells. These data suggest that the balance between S1P1and S1P2signaling regulates the homeostasis of microvascular permeability in the peripheral circulation and, thus, may affect total peripheral vascular resistance.
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Yoon, Chang Min, Bok Sil Hong, Hyung Geun Moon, Seyoung Lim, Pann-Ghill Suh, Yoon-Keun Kim, Chi-Bom Chae, and Yong Song Gho. "Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways." Blood 112, no. 4 (August 15, 2008): 1129–38. http://dx.doi.org/10.1182/blood-2007-11-125203.
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Abstract The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca2+ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference–mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122, and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca2+ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/Gi/phospholipase C/Ca2+ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors.
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Zhang, Yujin, Shushan Zhao, Hongyu Wu, Xia Hu, Renna Luo, Nicholas Parchim, Rodney E. Kellems, and Yang Xia. "Sphingosine 1-Phosphate (S1P)/S1P Receptor 1 Pathway Has an Essential Role for Sickle Cell Disease." Blood 124, no. 21 (December 6, 2014): 4063. http://dx.doi.org/10.1182/blood.v124.21.4063.4063.
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Abstract Sickle cell disease (SCD) is a devastating hemolytic genetic disorder associated with high morbidity and mortality. In order to understand the pathogenesis of this disease, we have conducted non-biased metabolomic screening and found that circulating sphingosine-1-phosphate (S1P) was significantly elevated in mice and patients with SCD. S1P is an important bioactive lipid signaling molecule known to regulate inflammation. Our previous study demonstrated that reduced S1P level in plasma and erythrocytes by treatment with sphingosine kinase 1 (SPHK1) inhibitor, PF-543, significantly decreased sickling cells, hemolysis and inflammation in SCD mouse model, which indicated that S1P may play an important role in an SCD complication, especially in inflammation. S1P engages five G-protein coupled receptors known as S1PR1-5. Targeting S1P signaling has been successfully applied in the treatment of the autoimmune disease-multiple sclerosis with the compound named FTY720. In order to understand the roles of S1P/S1PRs signal pathway in pathophysiology of SCD, we treated SCD mice with S1P receptors antagonist FTY720. The results showed that FTY720 successfully inhibited S1P receptors, especially S1P1 expression on immune cells from thymus and lymph node (P<0.05). Circulating white blood cells and inflammatory cytokines, such as CRP, IL-1β, TNF-α and IL-6, also decreased significantly measured by ELSIA kit. Additionally, FTY720 treatment significantly ameliorated organ damage. To investigate the roles of S1P1 receptor in SCD, we treated SCD mice with S1P1 specific antagonist, SEW2871. The results demonstrated that circulating white blood cells and inflammatory cytokines reduced significantly. Histologic studies revealed that the necrosis and congestion of multiple organs including kidney, lung and spleen were substantially reduced by SEW2841.Our studies demonstrate the elevated circulating S1P signaling via its receptor (likely S1PR1) directly contributes to inflammation and multiple tissue damage. Thus, it provides strong evidence that S1P/S1P1 pathway is likely a therapeutic target for SCD. Disclosures No relevant conflicts of interest to declare.
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Koch, Alexander, Manuel Jäger, Anja Völzke, Georgios Grammatikos, Dagmar Meyer zu Heringdorf, Andrea Huwiler, and Josef Pfeilschifter. "Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration." Biological Chemistry 396, no. 6-7 (June 1, 2015): 803–12. http://dx.doi.org/10.1515/hsz-2014-0288.
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Abstract Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1–5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells.
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El-Shewy, Hesham M., Mimi Sohn, Parker Wilson, Mi Hye Lee, Samar M. Hammad, Louis M. Luttrell, and Ayad A. Jaffa. "Low-Density Lipoprotein Induced Expression of Connective Tissue Growth Factor via Transactivation of Sphingosine 1-Phosphate Receptors in Mesangial Cells." Molecular Endocrinology 26, no. 5 (May 1, 2012): 833–45. http://dx.doi.org/10.1210/me.2011-1261.
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Abstract The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease. We recently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL-stimulated activation of ERK1/2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or down-regulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1/2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P1/S1P3 receptor antagonist VPC23019 significantly inhibited activation of ERK1/2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1/2 and JNK by stimulating SK1-dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1/2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1-dependent S1P receptor transactivation is upstream of ERK1/2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells.
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Damirin, Alatangaole, Hideaki Tomura, Mayumi Komachi, Jin-Peng Liu, Chihiro Mogi, Masayuki Tobo, Ju-Qiang Wang, et al. "Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 5 (May 2007): H2513—H2522. http://dx.doi.org/10.1152/ajpheart.00865.2006.
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The migration of vascular smooth muscle cells (SMCs) is a hallmark of the pathogenesis of atherosclerosis and restenosis after angioplasty. Plasma low-density lipoprotein (LDL), but not high-density lipoprotein (HDL), induced the migration of human coronary artery SMCs (CASMCs). Among bioactive lipids postulated to be present in LDL, lysophosphatidic acid (LPA) appreciably mimicked the LDL action. In fact, the LDL-induced migration was markedly inhibited by pertussis toxin, an LPA receptor antagonist Ki-16425, and a small interfering RNA (siRNA) targeted for LPA1 receptors. Moreover, LDL contains a higher amount of LPA than HDL does. HDL markedly inhibited LPA- and platelet-derived growth factor (PDGF)-induced migration, and sphingosine 1-phosphate (S1P), the content of which is about fourfold higher in HDL than in LDL, mimicked the HDL action. The inhibitory actions of HDL and S1P were suppressed by S1P2 receptor-specific siRNA. On the other hand, the degradation of the LPA component of LDL by monoglyceride lipase or the antagonism of LPA receptors by Ki-16425 allowed LDL to inhibit the PDGF-induced migration. The inhibitory effect of LDL was again suppressed by S1P2 receptor-specific siRNA. In conclusion, LPA/LPA1 receptors and S1P/S1P2 receptors mediate the stimulatory and inhibitory migration response to LDL and HDL, respectively. The balance of not only the content of LPA and S1P in lipoproteins but also the signaling activity between LPA1 and S1P2 receptors in the cells may be critical in determining whether the lipoprotein is a positive or negative regulator of CASMC migration.
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&NA;. "INTERNALIZATION OF THE S1P-1 RECEPTOR IS MEDIATED BY AGONISTS AND NOT BY ANTAGONISTS BUT DOES NOT REQUIRE INTRACELLULAR SIGNALING." Transplantation 82, Suppl 2 (July 2006): 426–27. http://dx.doi.org/10.1097/00007890-200607152-01067.
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Pelz, Andreas, Hanne Schaffert, Radharani Diallo, Falk Hiepe, Andreas Meisel, and Siegfried Kohler. "S1P receptor antagonists fingolimod and siponimod do not improve the outcome of experimental autoimmune myasthenia gravis mice after disease onset." European Journal of Immunology 48, no. 3 (December 19, 2017): 498–508. http://dx.doi.org/10.1002/eji.201747187.
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Germinario, Elena, Samantha Peron, Luana Toniolo, Romeo Betto, Francesca Cencetti, Chiara Donati, Paola Bruni, and Daniela Danieli-Betto. "S1P2 receptor promotes mouse skeletal muscle regeneration." Journal of Applied Physiology 113, no. 5 (September 1, 2012): 707–13. http://dx.doi.org/10.1152/japplphysiol.00300.2012.
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Sphingosine 1-phosphate is a bioactive lipid that modulates skeletal muscle growth through its interaction with specific receptors localized in the cell membrane of muscle fibers and satellite cells. This study analyzes the role of S1P2 receptor during in vivo regeneration of soleus muscle in two models of S1P2 deficiency: the S1P2-null mouse and wild-type mice systemically treated with the S1P2 receptor antagonist JTE-013. To stimulate regeneration, muscle degeneration was induced by injecting into soleus muscle the myotoxic drug notexin. Both ablation of S1P2 receptor and its functional inactivation delayed regeneration of soleus muscle. The exogenous supplementation of S1P or its removal, by a specific antibody, two conditions known to stimulate or inhibit, respectively, soleus muscle regeneration, were without effects when the S1P2 receptor was absent or inactive. The delayed regeneration was associated with a lower level of myogenin, a muscle differentiation marker, and reduced phosphorylation of Akt, a key marker of muscle growth. Consistently, silencing of S1P2 receptor abrogated the pro-myogenic action of S1P in satellite cells, paralleled by low levels of the myogenic transcription factor myogenin. The study indicates that S1P2 receptor plays a key role in the early phases of muscle regeneration by sustaining differentiation and growth of new-forming myofibers.
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Igawa, Satomi, Jae Eun Choi, Zhenping Wang, Yu-Ling Chang, Chia-Chi Wu, Tyler Werbel, Akemi Ishida-Yamamoto, and Anna Di Nardo. "Sphingosine 1-phosphate is a harbinger of S. aureus invasion and activates host defense in epithelial barriers." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 126.30. http://dx.doi.org/10.4049/jimmunol.202.supp.126.30.
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Abstract Background Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator generated in the skin when cell membrane or barrier components are damaged. S1P regulates diverse cell activities via S1P receptors (S1PR). Keratinocytes express S1PR1–5. Although it is known that S1PRs control keratinocyte differentiation, apoptosis and wound healing, S1PR functions in keratinocyte infections are not fully elucidated. We hypothesized that S1P and S1PR-axis in keratinocytes works as a biosensor for bacterial invasion. Methods The expression of S1PRs were studied by immunofluorescence and qPCR. Cytokine transcription and secretion were detected by qPCR and ELISA, respectively. siRNA and S1PR2 antagonist, JTE013, were used to test the different S1PR functions. The S1P synthesis was tested by ATP depletion assay and ELISA. Results We found a high epidermal S1PR1 and 2 expressions in human impetigo skin. In vitro, in normal human epidermal keratinocytes (NHEK), S. aureus bacterial supernatant not only induced S1P production but also increased S1PR2 transcription and TNFα, IL36γ, 6 and 8 transcriptions, confirming our in vivo observation. S1P directly increased NHEK IL36γ, TNFα and IL8 expression, but not IL6. In both, S1P and S. aureus bacterial supernatant treated NHEK, S1PR1 knock down reduced IL36γ, TNFα and IL8 transcription, while S1PR2 antagonist, JTE013, blocked their protein secretion. Conclusions We proved that, during infections, keratinocytes communicate the infection by sensing S1P release and respond to it using receptors S1PR1 and 2, releasing pro-inflammatory cytokines.
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Cohan, Stanley, Elisabeth Lucassen, Kyle Smoot, Justine Brink, and Chiayi Chen. "Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article." Biomedicines 8, no. 7 (July 18, 2020): 227. http://dx.doi.org/10.3390/biomedicines8070227.
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Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS.
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Whetzel, Angela M., David T. Bolick, and Catherine C. Hedrick. "Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3." American Journal of Physiology-Cell Physiology 296, no. 2 (February 2009): C339—C345. http://dx.doi.org/10.1152/ajpcell.00293.2008.
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Endothelial activation is a key early event in vascular complications of Type 1 diabetes. The nonobese diabetic (NOD) mouse is a well-characterized model of Type 1 diabetes. We previously reported that Type 1 diabetic NOD mice have increased endothelial activation, with increased production of monocyte chemoattractant protein (MCP)-1 and IL-6, and a 30% increase of surface VCAM-1 expression leading to a fourfold increase in monocyte adhesion to the endothelium. Sphingosine-1-phosphate (S1P) prevents monocyte:endothelial interactions in these diabetic NOD mice. Incubation of diabetic NOD endothelial cells (EC) with S1P (100 nmol/l) reduced ERK1/2 phosphorylation by 90%, with no significant changes in total ERK1/2 protein. In the current study, we investigated the mechanism of S1P action on ERK1/2 to reduce activation of diabetic endothelium. S1P caused a significant threefold increase in mitogen-activated kinase phosphatase-3 (MKP-3) expression in EC. MKP-3 selectively regulates ERK1/2 activity through dephosphorylation. Incubation of diabetic NOD EC with S1P and the S1P1-selective agonist SEW2871 significantly increased expression of MKP-3 and reduced ERK1/2 phosphorylation, while incubation with the S1P1/S1P3 antagonist VPC23019 decreased the expression of MKP-3, both results supporting a role for S1P1 in MKP-3 regulation. To mimic the S1P-mediated induction of MKP-3 diabetic NOD EC, we overexpressed MKP-3 in human aortic endothelial cells (HAEC) cultured in elevated glucose (25 mmol/l). Overexpression of MKP-3 in glucose-cultured HAEC decreased ERK1/2 phosphorylation and resulted in decreased monocyte:endothelial interactions in a static monocyte adhesion assay. Finally, we used small interfering RNA to MKP-3 and observed increased monocyte adhesion. Moreover, S1P was unable to inhibit monocyte adhesion in the absence of MKP-3. Thus, one mechanism for the anti-inflammatory action of S1P in diabetic EC is inhibition of ERK1/2 phosphorylation through induction of MKP-3 expression via the S1P-S1P1 receptor axis.
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Schwalm, Stephanie, Tankica Maneva Timcheva, Iuliia Filipenko, Mahsa Ebadi, Lotte P. Hofmann, Uwe Zangemeister-Wittke, Josef Pfeilschifter, and Andrea Huwiler. "Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts." Biological Chemistry 396, no. 6-7 (June 1, 2015): 813–25. http://dx.doi.org/10.1515/hsz-2014-0289.
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Abstract Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.
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Kalhori, Veronica, Melissa Magnusson, Muhammad Yasir Asghar, Ilari Pulli, and Kid Törnquist. "FTY720 (Fingolimod) attenuates basal and sphingosine-1-phosphate-evoked thyroid cancer cell invasion." Endocrine-Related Cancer 23, no. 5 (May 2016): 457–68. http://dx.doi.org/10.1530/erc-16-0050.
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The bioactive lipid sphingosine-1-phosphate (S1P) is a potent inducer of ML-1 thyroid cancer cell migration and invasion. It evokes migration and invasion by activating S1P receptor 1 and 3 (S1P1,3) and downstream signaling intermediates as well as through cross-communication with vascular endothelial growth factor receptor 2 (VEGFR2). However, very little is known about the role of S1P receptors in thyroid cancer. Furthermore, the currently used treatments for thyroid cancer have proven to be rather unsuccessful. Thus, due to the insufficiency of the available treatments for thyroid cancer, novel and targeted therapies are needed. The S1P receptor functional antagonist FTY720, an immunosuppressive drug currently used for treatment of multiple sclerosis, has shown promising effects as an inhibitor of cancer cell proliferation and invasion. In this study, we investigated the effect of FTY720 on invasion and proliferation of several thyroid cancer cell lines. We present evidence that FTY720 attenuated basal as well as S1P-evoked invasion of these cell lines. Furthermore, FTY720 potently downregulated S1P1, protein kinase Cα(PKCα), PKCβI, and VEGFR2. It also attenuated S1P-evoked phosphorylation of ERK1/2. Our results also showed that FTY720 attenuated S1P-induced MMP2 intracellular expression, S1P-induced secretion of MMP2 and MMP9, and decreased basal MMP2 and MMP9 activity. Moreover, in FTY720-treated cells, proliferation was attenuated, p21 and p27 were upregulated, and the cells were arrested in the G1 phase of the cell cycle. FTY720 attenuated cancer cell proliferation in the chick embryo chorioallantoic membrane assay. Thus, we suggest that FTY720 could be beneficial in the treatment of thyroid cancer.
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Pergolizzi, Jr., Joseph V., and Jo Ann LeQuang. "Sigma Antagonists for Treatment of Neuropathic Pain Syndromes in Cancer Patients: A Narrative Review." Journal of Cancer Research Updates 11 (October 27, 2022): 70–77. http://dx.doi.org/10.30683/1929-2279.2022.11.10.
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Almost 40% of cancer patients have neuropathic pain or mixed pain with a neuropathic component, which can be intense, debilitating, and challenging to treat. New studies on sigma receptors show these enigmatic ligand-binding protein chaperones may be helpful drug targets for new pharmacologic options to reduce many types of neuropathies, including chemotherapy-induced peripheral neuropathy (CIPN) and other cancer-related neuropathic pain syndromes. Our objective was to review the literature, including preclinical findings, in support of sigma-1 receptor (S1R) antagonists in reducing neuropathic pain and sigma-2 receptor (S2R) agonists for neuroprotection. The mechanisms behind these effects are not yet fully elucidated. The role of S1R antagonists in treating CIPN appears promising. In some cases, combination therapy of an opioid—which is a true analgesic—with a S1R antagonist, which is an anti-hyperalgesic and anti-allodynic agent, has been proposed. Of interest, but not well studied is whether or not S1R antagonists might be effective in treating CIPN in patients with pre-existing peripheral diabetic neuropathy. While neuropathic syndromes may occur with hematologic cancers, the role of S1R agonists may be effective. Sigma receptors are being actively studied now for a variety of conditions ranging from Alzheimer’s disease to Parkinson’s disease as well as neuropathic pain.
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Curry, F. E., J. F. Clark, and R. H. Adamson. "Erythrocyte-derived sphingosine-1-phosphate stabilizes basal hydraulic conductivity and solute permeability in rat microvessels." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 7 (October 1, 2012): H825—H834. http://dx.doi.org/10.1152/ajpheart.00181.2012.
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Exogenous sphingosine-1-phosphate (S1P), a lipid mediator in blood, attenuates acute microvascular permeability increases via receptor S1P1 to stabilize the endothelium. To evaluate the contribution of erythrocytes as an endogenous source of S1P to the regulation of basal permeability, we measured permeability coefficients in intact individually perfused venular microvessels of rat mesentery. This strategy also enabled the contributions of other endogenous S1P sources to be evaluated. Apparent permeability coefficients ( PS) to albumin and α-lactalbumin and the hydraulic conductivity of mesenteric microvessels were measured in the presence or absence of rat erythrocytes or rat erythrocyte-conditioned perfusate. Rat erythrocytes added to the perfusate were the principal source of S1P in these microvessels. Basal PS to albumin was stable and typical of blood-perfused microvessels (mean 0.5 × 10−6 cm/s) when erythrocytes or erythrocyte-conditioned perfusates were present. When they were absent, PS to albumin or α-lactalbumin increased up to 40-fold (over 10 min). When exogenous S1P was added to perfusates, permeability returned to levels comparable with those seen in the presence of erythrocytes. Addition of SEW 2871, an agonist specific for S1P1, in the absence of red blood cells reduced PSBSA (40-fold reduction) toward basal. The specific S1P1 receptor antagonist (W-146) reversed the stabilizing action of erythrocytes and increased permeability (27-fold increase) in a manner similar to that seen in the absence of erythrocytes. Erythrocytes are a primary source of S1P that maintains normal venular microvessel permeability. Absence of erythrocytes or conditioned perfusate in in vivo and in vitro models of endothelial barriers elevates basal permeability.
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Oskeritzian, Carole A., Megan M. Price, Nitai C. Hait, Dmitri Kapitonov, Yves T. Falanga, Johanna K. Morales, John J. Ryan, Sheldon Milstien, and Sarah Spiegel. "Essential roles of sphingosine-1–phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema." Journal of Experimental Medicine 207, no. 3 (March 1, 2010): 465–74. http://dx.doi.org/10.1084/jem.20091513.
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Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1–phosphate (S1P), a ligand for a family of G protein–coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P2 receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E–triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P2 antagonist JTE-013 and in S1P2-deficient mice, in contrast to anaphylaxis induced by administration of histamine or platelet-activating factor. Hence, S1P and S1P2 on mast cells are determinants of systemic anaphylaxis and associated pulmonary edema and might be beneficial targets for anaphylaxis attenuation and prophylaxis.
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dela Paz, Nathaniel G., Benoît Melchior, and John A. Frangos. "Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells." American Journal of Physiology-Cell Physiology 312, no. 4 (April 1, 2017): C428—C437. http://dx.doi.org/10.1152/ajpcell.00148.2016.
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Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/Gαq/11 pair in EC shear stress-induced mechanotransduction. We demonstrated that sphingosine 1-phosphate (S1P) stimulation causes a rapid dissociation at 0.5 min of Gαq/11 from its receptor S1P3, followed by an increased association within 2 min of GPCR kinase-2 (GRK2) and β-arrestin-1/2 with S1P3 in human coronary artery ECs, which are consistent with GPCR/Gαq/11 activation and receptor desensitization/internalization. The G protein activator AlF4 resulted in increased dissociation of Gαq/11 from S1P3, but no increase in association between S1P3 and either GRK2 or β-arrestin-1/2. The G protein inhibitor guanosine 5′-(β-thio) diphosphate (GDP-β-S) and the S1P3 antagonist VPC23019 both prevented S1P-induced activation. Shear stress also caused the rapid activation within 7 s of S1P3/Gαq/11. There were no increased associations between S1P3 and GRK2 or S1P3 and β-arrestin-1/2 until 5 min. GDP-β-S, but not VPC23019, prevented dissociation of Gαq/11 from S1P3 in response to shear stress. Shear stress did not induce rapid dephosphorylation of β-arrestin-1 or rapid internalization of S1P3, indicating no GPCR activation. These findings suggest that Gαq/11 participates in the sensing/transducing of shear stress independently of GPCR activation in ECs.
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Bandhuvula, Padmavathi, Norman Honbo, Guan-Ying Wang, Zhu-Qiu Jin, Henrik Fyrst, Meng Zhang, Alexander D. Borowsky, Lisa Dillard, Joel S. Karliner, and Julie D. Saba. "S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 5 (May 2011): H1753—H1761. http://dx.doi.org/10.1152/ajpheart.00946.2010.
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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia ( n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls ( n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity ( n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts ( n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P1 and S1P3 receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.
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Shah, Mithun Vinod, Ranran Zhang, Rosalyn Irby, Ravi Kothapalli, Xin Liu, Ty Arrington, Bryan Frank, Norman H. Lee, and Thomas P. Loughran. "Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes." Blood 112, no. 3 (August 1, 2008): 770–81. http://dx.doi.org/10.1182/blood-2007-11-121871.
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Abstract T-cell large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of CD3+CD8+ cells. Leukemic LGLs correspond to terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs) that escape Fas-mediated activation-induced cell death (AICD) in vivo. The gene expression signature of peripheral blood mononuclear cells from 30 LGL leukemia patients showed profound dysregulation of expression of apoptotic genes and suggested uncoupling of activation and apoptotic pathways as a mechanism for failure of AICD in leukemic LGLs. Pathway-based microarray analysis indicated that balance of proapoptotic and antiapoptotic sphingolipid-mediated signaling was deregulated in leukemic LGLs. We further investigated sphingolipid pathways and found that acid ceramidase was constitutively overexpressed in leukemic LGLs and that its inhibition induced apoptosis of leukemic LGLs. We also showed that S1P5 is the predominant S1P receptor in leukemic LGLs, whereas S1P1 is down-regulated. FTY720, a functional antagonist of S1P-mediated signaling, induced apoptosis in leukemic LGLs and also sensitized leukemic LGLs to Fas-mediated death. Collectively, these results show a role for sphingolipid-mediated signaling as a mechanism for long-term survival of CTLs. Therapeutic targeting of this pathway, such as use of FTY720, may have efficacy in LGL leukemia.