Sphingolipids are major constituents of all cellular membranes, and in addition to their structural functions, some sphingolipids have also signalling functions. One of those is sphingosine-1-phosphate (S1P), which is formed by phosphorylation of sphingosine by sphingosine kinases (SphK1 and SphK2) in cytosol and ER, and deactivated by sphingosine phosphatases and sphingosine phosphate lyase. Ceramidase releases sphingosine from ceramides. Ceramide has pro-apoptotic properties, and ceramide-1-phosphate is another signalling molecule. S1P can also be formed extracellularly by autotaxin from sphingosine phosphoryl choline. S1P modulates, among other things, angiogenesis, cardiac function, and inflammation.
Cytosolic SphK1 in erythrocytes is the major source of circulating S1P. SphK2 is mainly responsible for intracellular S1P pools.
Sphingosine-1-phosphate is endogenous agonist of S1P receptors, that are G protein-coupled receptors, and divided into five subtypes (S1PR1-5). S1PR1, S1PR2, and S1PR3 are expressed in practically all cells, although with highest expression in immune cells. S1PR1 on astrocytes, neural stem cells, and B and T cells regulate the cell migration; on cardiomyocytes they affect the β-AR signalling; on endothelial cells S1PR1 regulates the vessel permeability. S1PR2 are involved in matrix remodelling, angiogenesis, and fibroblast function, and mast cell degranulation. S1PR4 is expressed in lymphoid and hematopoietic tissues. S1PR5 is expressed mainly in the white matter in the brain.
[11C]TZ3321 is a S1PR1-specific PET tracer (Liu et al., 2016; Jin et al., 2017), and it has been used in small animal models to study vascular injury and MS. Fluorine-18 labelled S1PR1 radioligands are under development (Shaikh et al., 2015; Luo et al., 2018).
Chalfant C, Del Poeta M (eds.): Sphingolipids as Signaling and Regulatory Molecules. Springer, 2010. ISBN: 978-1-4419-6740-4.
Gulbins E, Petrache I (eds.): Sphingolipids: Basic Science and Drug Development. Springer, 2013. doi: 10.1007/978-3-7091-1368-4.
Huwiler A, Pfeilschifter J. Sphingolipid signaling in renal fibrosis. Matrix Biol. 2018 (in press). doi: 10.1016/j.matbio.2018.01.006.
Karunakaran I, van Echten-Deckert G. Sphingosine 1-phosphate - a double edged sword in the brain. Biochim Biophys Acta 2017; 1859(9 Pt B): 1573-1582. doi: 10.1016/j.bbamem.2017.03.008.
Mendelson K, Evans T, Hla T. Sphingosine 1-phosphate signalling. Development 2014; 141(1): 5-9. doi: 10.1242/dev.094805.
Oldstone MBA, Rosen H (eds.): Sphingosine-1-Phosphate Signaling in Immunology and Infectious Diseases. Springer, 2014. doi: 10.1007/978-3-319-05879-5.
Created at: 2018-01-23
Updated at: 2018-05-21
Written by: Vesa Oikonen