S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.
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Research Article|
September 12 2012
Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate
Yugesh Kharel;
Yugesh Kharel
1
*Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Mithun Raje;
Mithun Raje
1
†Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, U.S.A.
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Ming Gao;
Ming Gao
†Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, U.S.A.
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Amanda M. Gellett;
Amanda M. Gellett
*Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Jose L. Tomsig;
Jose L. Tomsig
*Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Kevin R. Lynch;
*Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, U.S.A.
2To whom correspondence should be addressed (email krl2z@virginia.edu).
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Webster L. Santos
†Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, U.S.A.
2To whom correspondence should be addressed (email krl2z@virginia.edu).
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Publisher: Portland Press Ltd
Received:
April 12 2012
Revision Received:
June 05 2012
Accepted:
June 29 2012
Accepted Manuscript online:
June 29 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 447 (1): 149–157.
Article history
Received:
April 12 2012
Revision Received:
June 05 2012
Accepted:
June 29 2012
Accepted Manuscript online:
June 29 2012
Citation
Yugesh Kharel, Mithun Raje, Ming Gao, Amanda M. Gellett, Jose L. Tomsig, Kevin R. Lynch, Webster L. Santos; Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate. Biochem J 1 October 2012; 447 (1): 149–157. doi: https://doi.org/10.1042/BJ20120609
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