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Research ArticleCellular and Molecular

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Yugesh Kharel, Emily A. Morris, Molly D. Congdon, Steven B. Thorpe, Jose L. Tomsig, Webster L. Santos and Kevin R. Lynch
Journal of Pharmacology and Experimental Therapeutics October 2015, 355 (1) 23-31; DOI: https://doi.org/10.1124/jpet.115.225862
Yugesh Kharel
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Emily A. Morris
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Molly D. Congdon
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Steven B. Thorpe
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Jose L. Tomsig
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Webster L. Santos
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Kevin R. Lynch
Department of Pharmacology, University of Virginia, Charlottesville, Virginia (Y.K., J.L.T., K.R.L.); Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia (E.A.M., M.D.C., W.L.S.); and SphynKx Therapeutics LLC, Charlottesville, Virginia (S.B.T.)
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Abstract

Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitor–treated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels.

Footnotes

    • Received May 14, 2015.
    • Accepted July 23, 2015.
  • This study was supported by grants from the National Institutes of Health [Grants R01 GM067958, R01 GM104366, and R43 GM106495]. W.L.S. and K.R.L. are among the cofounders of SphynKx Therapeutics LLC.

  • dx.doi.org/10.1124/jpet.115.225862.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 1
1 Oct 2015
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Research ArticleCellular and Molecular

SphK2 and Blood S1P

Yugesh Kharel, Emily A. Morris, Molly D. Congdon, Steven B. Thorpe, Jose L. Tomsig, Webster L. Santos and Kevin R. Lynch
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 23-31; DOI: https://doi.org/10.1124/jpet.115.225862

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Research ArticleCellular and Molecular

SphK2 and Blood S1P

Yugesh Kharel, Emily A. Morris, Molly D. Congdon, Steven B. Thorpe, Jose L. Tomsig, Webster L. Santos and Kevin R. Lynch
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 23-31; DOI: https://doi.org/10.1124/jpet.115.225862
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