The role of sphingosine 1-phosphate receptors in the treatment of demyelinating diseases

Sphingosine 1-phosphate receptors (S1PRs) are a family of G-protein coupled receptors composed of subtypes S1PR1-5 and activated by the endogenous ligand sphingosine 1-phosphate. S1PRs are modulated by the recently approved oral therapy for relapsing-remitting multiple sclerosis, called fingolimod (FTY720). The phosphorylated version of FTY720 (pFTY720) is a pan-S1PR agonist, with the exception of S1PR2. This drug promotes the internalization of S1PR1s in T cells and is said to act as a 'functional antagonist' making lymphocytes 'blind' to sphingosine 1-phosphate gradients and limiting cell egress from lymph nodes. This immunomodulatory effect of pFTY720 is proposed to be the prime mechanism by which this compound is efficacious in the treatment of multiple sclerosis. Importantly, however, S1PRs are also expressed in many other cell types, for example, cells of the cardiovascular system and the CNS. Studies have shown that pFTY720 enters the CNS and that modulation of S1PRs can alter the cellular physiology of neurons, astrocytes, microglia and oligodendrocytes. These works are suggestive of a potential role for S1PRs expressed in brain cells as targets for pFTY720. This article reviews the role of S1PRs in oligodendrocytes. The authors start by first debating whether pFTY720-mediated internalization of S1PRs causes 'functional antagonism' and/or 'pathway-specific continued signaling'. The authors then describe the signaling pathways that are modulated by S1PRs expressed in oligodendrocytes and also outline the role of S1PRs in oligodendrocyte differentiation, process extension, survival and migration. Finally, the authors discuss the in vitro studies that suggest pFTY720 promotes myelination state versus the in vivo studies that suggest pFTY720 may not alter myelination. The authors conclude by suggesting that S1PRs in the CNS may be of potential use as drug targets not only for multiple sclerosis, but possibly for a number of other demyelinating disorders.