Abstract
Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.
Highlights
S1P Metabolism and SignalingThree decades ago, sphingosine 1-phosphate (S1P) was identified as an intracellular signaling agent in relation to calcium release from intracellular stores and metabolic adaptations [1]
Fine tuning of S1P-S1P receptor (S1PR) signaling may occur via post-translational modifications, e.g., through palmitoylation by the palmitoyltransferase DHHC5 (DHHC5) [73] and, at some point, termination of the signaling cascade may be achieved by β-arrestin-dependent recruitment of G protein-coupled receptor kinase 2 (GRK2), which phosphorylates S1PR, resulting in dynamin and moesin dependent establishment of the endosome [74,75,76,77,78,79]
We described the complexities of the sphingosine 1-phosphate (S1P) signaling in neurological conditions in reflection of currently available S1P signaling targeted drugs
Summary
Sphingosine 1-phosphate (S1P) was identified as an intracellular signaling agent in relation to calcium release from intracellular stores and metabolic adaptations [1]. The balance between sphingosine and S1P, both metabolites of its precursor ceramide, and their subsequent activation of effector kinases were shown to matter in imposing regulatory effects in the determination of whether a cell is destined for cell death or proliferation [2]. The sphingolipid metabolism is almost as complex as its protean intricacies to signaling pathways
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