Regulation and functions of sphingosine kinases in the brain

Abstract

It has long been known that sphingolipids, especially sphingomyelin, a principal component of myelin, are highly enriched in the central nervous system and are structural components of all eukaryotic cell membranes. In the last few years, substantial evidence has accumulated from studies of many types of cells demonstrating that in addition to their structural roles, their breakdown products form a new class of signaling molecules with potent and myriad regulatory effects on essentially every cell in the body. While the sphingolipid metabolites sphingosine and its precursor ceramide have been associated with cell growth arrest and apoptosis, sphingosine-1-phosphate (S1P) enhances proliferation, differentiation, and cell survival as well as regulates many physiological and pathological processes. The relative levels of these three interconvertible sphingolipid metabolites, and thus cell fate, are strongly influenced by the activity of sphingosine kinases, of which there are two isoforms, designated SphK1 and SphK2, the enzymes that phosphorylate sphingosine to produce S1P. Not much is yet known of the importance of S1P in the central nervous system. Therefore, this review is focused on current knowledge of regulation of SphK1 and SphK2 on both transcriptional and post-translational levels and the functions of these isozymes and their product S1P and its receptors in the central nervous system.

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…With this goal in mind we synthesized a BODIPY-derivatized analog of DH376 termed DH379 (6) and confirmed that this probe labeled recombinant DAGLα and DAGLβ and detected these enzymes in the mouse brain membrane proteome (SI Appendix, Fig. S2).…”

“…This "on-demand" model for production implicates lipid biosynthetic enzymes as major regulators of chemical signaling in the central nervous system (CNS). In support of this premise, the enzymes that produce several classes of lipid transmitters, including lysophospholipids (6), eicosanoids (7), and endocannabinoids (8,9), are highly expressed in the nervous system and play important roles in brain development, synaptic plasticity, and the modulation of complex behaviors. For example, the diacylglycerol (DAG) lipase enzymes DAGLα and DAGLβ (10) produce the endocannabinoid 2-arachidonoylglycerol (2-AG) (11,12), and the constitutive genetic disruption of DAGLα lowers brain 2-AG and arachidonic acid (AA) content (13,14), resulting in impaired synaptic plasticity (13,14), hypophagia (15), enhanced anxiety and fear responses (16,17), and propensity for spontaneous seizures (15).…”

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

“…It is phosphorylated intracellularly by sphingosine kinase 2 but not sphingosine kinase 1, producing FTY720-phosphate (FTY720-P) (Paugh et al, 2003). FTY720-P acts as a functional analog of the endogenous ligand sphingosine-1-phosphate (S1P), which has pleiotropic effects in angiogenesis (Limaye, 2008), neurological excitability (Bryan et al, 2008), cell differentiation (Moriue et al, 2008;Saddoughi et al 2008;Qin et al, 2010) and inflammation (Huwiler and Pfeilschifter, 2008;Spiegel and Milstien, 2011). Therefore, in its phosphorylated state, FTY720 has been proposed to interfere with functions mediated by S1P and is thus investigated in basic research.…”

Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways

“…The compound does not impair T-or B-lymphocyte activation, proliferation, or effector functions at clinically relevant concentrations (Pinschewer et al, 2000). Fingolimod may also have direct effects in the central nervous system because sphingosine 1-phosphate receptors are present in this tissue (Bryan et al, 2008), and (S)-fingolimod phosphate can be assumed to be present as well, based on results in the rat (Foster et al, 2007;Novartis, unpublished data).…”