Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator

Ter Braak, Michael; Claas, Ralf Frederik; Hegen, Bianca; Labocha, Sandra; Ferreirós, Nerea; Pfeilschifter, Josef; Huwiler, Andrea; van Echten-Deckert, Gerhild; Meyer Zu Heringdorf, Dagmar (2011). Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator. Biochemical pharmacology, 81(5), pp. 617-25. New York, N.Y.: Elsevier 10.1016/j.bcp.2010.12.002

Full text not available from this repository. (Request a copy)

Sphingosine-1-phosphate (S1P) acts as high affinity agonist at specific G-protein-coupled receptors, S1P(1-5), that play important roles e.g. in the cardiovascular and immune systems. A S1P receptor modulating drug, FTY720 (fingolimod), has been effective in phase III clinical trials for multiple sclerosis. FTY720 is a sphingosine analogue and prodrug of FTY720-phosphate, which activates all S1P receptors except S1P(2) and disrupts lymphocyte trafficking by internalizing the S1P(1) receptor. Cis-4-methylsphingosine (cis-4M-Sph) is another synthetic sphingosine analogue that is readily taken up by cells and phosphorylated to cis-4-methylsphingosine-1-phosphate (cis-4M-S1P). Therefore, we analysed whether cis-4M-Sph interacted with S1P receptors through its metabolite cis-4M-S1P in a manner similar to FTY720. Indeed, cis-4M-Sph caused an internalization of S1P receptors, but differed from FTY720 as it acted on S1P(2) and S1P(3) and only weakly on S1P(1), while FTY720 internalized S1P(1) and S1P(3) but not S1P(2). Consequently, pre-incubation with cis-4M-Sph specifically desensitized S1P-induced [Ca(2+)](i) increases, which are mediated by S1P(2) and S1P(3), in a time- and concentration-dependent manner. This effect was not shared by sphingosine or FTY720, indicating that metabolic stability and targeting of S1P(2) receptors were important. The desensitization of S1P-induced [Ca(2+)](i) increases was dependent on the expression of SphKs, predominantly of SphK2, and thus mediated by cis-4M-S1P. In agreement, cis-4M-S1P was detected in the supernatants of cells exposed to cis-4M-Sph. It is concluded that cis-4M-Sph, through its metabolite cis-4M-S1P, acts as a S1P receptor modulator and causes S1P receptor internalization and desensitization. The data furthermore help to define requirements for sphingosine kinase substrates as S1P receptor modulating prodrugs.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea








Factscience Import

Date Deposited:

04 Oct 2013 14:09

Last Modified:

17 Mar 2015 19:09

Publisher DOI:


PubMed ID:


Web of Science ID:


URI: (FactScience: 201113)

Actions (login required)

Edit item Edit item
Provide Feedback