Pharmacology of the sphingosine-1-phosphate (S1P) signalling system

Dagmar Meyer zu Heringdorf, Hans Vienken, Nicole Kämpfer-Kolb, Agnes Rudowski, Jonas Düdder

The formation and degradation of S1P is highly organized in space and time. S1P is formed from sphingosine (Sph) by sphingosine kinases (SphKs). It can be dephosphorylated by lipid phosphate phosphatases (LPPs) or specific S1P phosphatases (SPPs). S1P lyase (SPL) cleaves S1P irreversibly.


The lysophospholipid, sphingosine-1-phosphate (S1P), is a ubiquitous autocrine and paracrine mediator that regulates cell growth and survival, cell motility and adhesion in many cell types. Extracellular S1P activates specific G-protein-coupled receptors, termed S1P1-5


These receptors are widely expressed and form a network regulating developmental and adaptive processes such as heart beat, vasculogenesis, vascular tone/contractility and permeability, inner ear functionality, lymphocyte trafficking, neurite retraction/outgrowth, neural tube formation, inflammation, artherosclerosis, tumour growth and chemoresistance.
Intracellular S1P can stimulate cell growth and survival and mobilizes Ca2+ from thapsigargin-sensitive Ca2+ stores independently of G-protein-coupled S1P receptors. As direct intracellular targets of S1P, class I histone deacetylases (HDACs), the ubiquitin ligase TRAF2, mitochondrial prohibitin-2, and a few other proteins have been described.

Our work focuses on regulation and functional roles of sphingosine kinases and on the targets and activities of intracellular S1P, in particular with respect to regulation of cellular Ca2+ homeostasis.

I. Regulation and functional roles of sphingosine kinases

The two sphingosine kinase isoforms, SphK1 and SphK2, are regulated transcriptionally and posttrancriptionally in a complex manner.
We focused on the regulation of sphingosine kinases by G-protein-coupled receptors and observed that Gq-coupled receptors, such as the M3 muscarinic acetylcholine receptor or the bradykinin B2 receptor, induce a rapid translocation of SphK1 from the cytosol to the plasma membrane in many cell types. A functional consequence can be cross-activation of G-protein-coupled S1P receptors, thus linking Gq-coupled receptors to Gi and/or G12/13 signalling pathways (cit. 1).
In our ongoing work, we further analyse the molecular mechanism of Gq-mediated SphK1 translocation and its functional role for Gq-mediated signalling in the cardiovascular system.
Translocation of GFP-hSphK1 induced by activation of the M3 muscarinic receptor in HEK-293 cells. Carbachol was added at ~15 s.
(click to start movie)

Translocation of YFP-mSphK1 in vascular smooth muscle (A10) cells. Carbachol was added at
~ 30 s.
(click to start movie)

II. Targets and activities of intracellular S1P; regulation of cellular Ca2+ homeostasis by S1P

Many diverse membrane receptors can rapidly stimulate sphingosine kinase activity and cellular S1P production. This rapid S1P formation has been implicated in receptor-stimulated Ca2+ mobilization. Intracellular S1P can mobilize Ca2+ from thapsigargin-sensitive stores independently of G-protein-coupled S1P receptors, independently of IP3 binding sites of the IP3-gated endoplasmic reticulum Ca2+ channel, and independently of ryanodine receptors. Interestingly, of the so far identified direct intracellular target sites of S1P, none is involved in Ca2+ mobilization and thus the target for this well-characterized activity of S1P remains unknown so far.

Recently, we have used S1P lyase-deficient cells, in which S1P accumulates, to study the effects of intracellular S1P. In S1P lyase-deficient fibroblasts, Ca2+ homeostasis was disturbed, as basal [Ca2+]i was elevated and agonist-induced [Ca2+]i increases as well as Ca2+ storage in thapsigargin-sensitive stores were enhanced. In these cells, S1P accumulated particularly in the nucleus. HDAC activity and the expression of HDACs 1 and 3, but not 2, were reduced, and acetylation of H3K9 was enhanced. We identified a link between reduced HDAC activity and dysregulation of Ca2+ homeostasis, as HDAC inhibitors differentially elevated basal [Ca2+]i and augmented stored Ca2+, and overexpression of HDAC1 or HDAC2 reduced basal [Ca2+]i (cit. 3).

In our ongoing work, we further analyse the interrelationship between intracellular S1P, HDAC inhibition/downregulation and cellular Ca2+ homeostasis in cells and tissues from Sgpl1-/- mice and with Sgpl1-siRNA.
(see also )

III. S1P receptor modulators; S1P export and transport

In further projects, we characterize novel S1P receptor modulators and analyse the cellular export and transport of S1P.

Lipid signalling links:

Signalling gateway

Supported by:

LOEWE Lipid Signalling Forschungszentrum Frankfurt (LiFF)
DFG: SFB 1039 Krankheitsrelevante Signaltransduktion durch Fettsäurederivate und Sphingolipide

Member of the Frankfurt International Research Graduate School for Translational Biomedicine (First)

Member of the Sphingolipid Club

Selected Publications
  1. Ter Braak M, Danneberg K, Lichte K, Liphardt K, Ktistakis NT, Pitson SM, Hla T, Jakobs KH, Meyer zu Heringdorf D (2009) Gaq-mediated plasma membrane translocation of sphingosine kinase-1 and cross-activation of S1P receptors.
    Biochim Biophys Acta 1791:357-370 .
  2. Ter Braak M, Claas RF, Hegen B, Labocha S, Ferreirós N, Pfeilschifter J, Huwiler A, van Echten-Deckert G, Meyer zu Heringdorf D (2011) Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator.
    Biochem Pharmacol 81:617-625.
  3. Ihlefeld K, Claas RF, Koch A, Pfeilschifter J, Meyer zu Heringdorf D (2012) Evidence for a link between histone deacetylation and Ca2+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts.
    Biochem J 447:457-464.
  4. Meyer zu Heringdorf D, Ihlefeld K, Pfeilschifter J (2013) Pharmacology of the sphingosine-1-phosphate signalling system. Handb Exp Pharmacol 215:239-253.
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