FTY720P inhibits the Na+/K+ ATPase in Caco-2 cells via S1PR2: PGE2 and NO are along the signaling pathway
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Elsevier Inc.
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Aims: Sphingosine-1-phosphate (S1P) has been implicated lately in inflammatory bowel disease which has diarrhea as one of its symptoms. Diarrhea is due to altered water movements as a result of altered electrolyte transport, and in particular sodium. Sodium movements are geared by the sodium gradient established by the Na+/K+ ATPase. The aim of this work was to investigate if S1P can modulate the activity of the ATPase, using Caco-2 cells as a model and the S1P analogue, FTY720P. Materials and methods: The activity of the ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain. Protein expression of the various S1P receptors was studied by western blot analysis. Key findings: Caco-2 cells were found to express mainly S1PR2 and S1PR3. FTY720P (7.5 nM) reduced significantly the activity of the Na+/K+ ATPase when applied for 15 min. This inhibitory effect disappeared in presence of JTE-013, a specific blocker of S1PR2, and indomethacin, an inhibitor of cyclooxygenase enzymes, and was mimicked by CYM5520, a S1PR2 agonist and by exogenous PGE2. The inhibitory effect of PGE2 did not appear when EP3 receptors were blocked or when a nitric oxide scavenger was added. RpcAMP, a PKA inhibitor, reduced the activity of the Na+/K+ ATPase, while dbcAMP, a PKA activator was without any effect and when added, abrogated the effect of PGE2. Significance: It was concluded that FTY720P inhibits the Na+/K+ ATPase via activation of S1PR2 and generation of PGE2 nitric oxide. © 2018 Elsevier Inc.
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Ep3, Fty720p, Na+/k+ atpase, No, Pge2, Blotting, western, Caco-2 cells, Dinoprostone, Humans, Indomethacin, Lysophospholipids, Nitric oxide, Organophosphates, Pyrazoles, Pyridines, Pyrroles, Receptors, lysosphingolipid, Signal transduction, Sodium-potassium-exchanging atpase, Sphingosine, 4 (2,6 dichloro 4 pyridinyl) 1 (1,3 dimethyl 4 isopropyl 1h pyrazolo[3,4 b]pyridin 6 yl)semicarbazide, Adenosine triphosphatase (potassium sodium), Fingolimod, Fty 720 p, Indometacin, Ouabain, Phosphate, Prostaglandin e receptor 3, Prostaglandin e2, Sphingosine 1 phosphate receptor, Sphingosine 1 phosphate receptor 2, Sphingosine 1 phosphate receptor 3, Unclassified drug, Cym-5520, Fty 720p, Lysophospholipid, Organophosphate, Pyrazole derivative, Pyridine derivative, Pyrrole derivative, S1pr2 protein, human, Sphingosine 1-phosphate, Antineoplastic activity, Article, Caco-2 cell line, Controlled study, Drug effect, Drug efficacy, Drug mechanism, Drug response, Enzyme activity, Enzyme inhibition, Human, Human cell, Protein expression, Western blotting, Analogs and derivatives, Antagonists and inhibitors, Metabolism