Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

Abstract

The central nervous system is characterized by a high content of sphingolipids and by a high diversity in terms of different structures. Stage- and cell-specific sphingolipid metabolism and expression are crucial for brain development and maintenance toward adult age. On the other hand, deep dysregulation of sphingolipid metabolism, leading to altered sphingolipid pattern, is associated with the majority of neurological and neurodegenerative diseases, even those totally lacking a common etiological background. Thus, sphingolipid metabolism has always been regarded as a promising pharmacological target for the treatment of brain disorders. However, any therapeutic hypothesis applied to complex amphipathic sphingolipids, components of cellular membranes, has so far failed probably because of the high regional complexity and specificity of the different biological roles of these structures. Simpler sphingosine-based lipids, including ceramide and sphingosine 1-phosphate, are important regulators of brain homeostasis, and, thanks to the relative simplicity of their metabolic network, they seem a feasible druggable target for the treatment of brain diseases. The enzymes involved in the control of the levels of bioactive sphingoids, as well as the receptors engaged by these molecules, have increasingly allured pharmacologists and clinicians, and eventually fingolimod, a functional antagonist of sphingosine 1-phosphate receptors with immunomodulatory properties, was approved for the therapy of relapsing-remitting multiple sclerosis. Considering the importance of neuroinflammation in many other brain diseases, we would expect an extension of the use of such analogs for the treatment of other ailments in the future. Nevertheless, many aspects other than neuroinflammation are regulated by bioactive sphingoids in healthy brain and dysregulated in brain disease. In this review, we are addressing the multifaceted possibility to address the metabolism and biology of bioactive sphingosine 1-phosphate as novel targets for the development of therapeutic paradigms and the discovery of new drugs.

Keywords: FTY720; fingolimod; sphingosine 1-phosphate; sphingosine 1-phosphate lyase; sphingosine 1-phosphate phosphatase; sphingosine 1-phosphate receptors; sphingosine kinase.

Figure 1

Chemical structures of sphingosine, ceramide, sphingosine 1-phosphate, galactosylceramide, sphingomyelin, and monosialoganglioside GM1.

Figure 2

Subcellular compartmentalization of sphingolipid metabolism. The endoplasmic reticulum (ER) is the subcellular site where the de novo ceramide (Cer) synthesis occurs (A). Here, the synthesis of the sphingoid bases (sphingosine) starts with the condensation of palmitoyl-CoA and serine, catalyzed by serine palmitoyltransferase (SPT). The product of this reaction is 3-ketodihydrosphingosine (3-kdhSo), which is later reduced to dihydrosphingosine (dhSo) via the action of 3-ketodihydrosphingosine reductase (KDSR). Then, dhSo is acylated generating dihydroceramide (dhCer). In humans, this reaction occurs through the activities of six different ceramide synthases (CerS). Dihydroceramide is then unsaturated to ceramide by the enzyme dihydroceramide desaturase 1 (DES1). At ER level, Cer is either transformed into GalCer () by CGalT (B) or delivered by ceramide transport protein (CERT) (C) or through vesicular transport (D) to the Golgi apparatus for the synthesis of sphingomyelin (SM ) by SMS1 and glucosylceramide (GlcCer ) by GCS (E). At the Golgi, GlcCer is transformed into lactosylceramide (LacCer ) and complex GSLs (e.g., GM3 ) (F), which are then delivered to the plasma membrane via Golgi vesicular transport (G). At the plasma membrane level, SM can be converted into ceramide by sphingomyelinase (SMase), ceramide can then be transformed into sphingosine (Sph) by ceramidase (CDase), and sphingosine is converted into sphingosine 1-phosphate (S1P ) by sphingosine kinases (SK1) (H). S1P is then transported across the membrane by specific transporters. Phosphorylation of sphingosine yielding to S1P because of the action of sphingosine kinase 2 (SK2) can occur at the mitochondria (I), nucleus (J), and ER (K). In the ER, S1P can be either irreversibly cleaved by S1P lyase or dephosphorylated back to sphingosine by a specific phosphatase (SPP1). Membrane sphingolipids are internalized via caveolae-dependent endocytosis and, in the lysosome, they are degraded by acidic forms of SMase and by different glycosidases (GCase) yielding ceramide that can be further hydrolyzed by the acid ceramidases (CDase) (L). The sphingosine formed in this reaction can escape the lysosome and can be metabolized to glycerophospholipids after phosphorylation by SK1 and cleavage by S1P lyase (SGPL) or it can be recycled for sphingolipid synthesis in the salvage pathway (M).

Figure 3

Extracellular and intracellular actions of S1P. Cells release S1P in the extracellular milieu through specific transporters [spinster homolog 2 (Spns2) or ABC transporters]. S1P in the extracellular milieu then binds to S1P receptors (S1P₁–S1P₅) located at the plasma membrane, thus inducing biological responses.

Figure 4

Comparative signaling pathways of S1P and FTY720-P. Both S1P (left panel) and FTY720-P (right panel) stimulate the internalization of S1P receptor. The receptor that binds S1P is recycled back to the cell surface, whereas FTY720-P causes irreversible internalization and degradation of bound S1P receptor.

Figure 5

Novel modulators of S1P receptors.