Function and Modulation of Sphingosine-1-Phosphate Receptors in the Central Nervous System

Sphingolipids, first discovered in the 1874 by Johann Thudicum, are one of the 8 recognized classes of lipids and are present in essentially all plants, animals, and fungi as well as some viruses and prokaryotes. In mammals’ sphingolipids are enriched in the central nervous system (CNS) where they play vital roles in tissue development, membrane structure, cell adhesion and recognition, and importantly signaling. A subset of sphingolipids has been shown to have bioactive properties including ceramide, glucosylceramide, and sphingosine but two sphingolipids in particular (ceramide-1-phosphate and sphingosine-1-phosphate) have been shown to exert their effects at least in part due to activation of cell surface expressed G protein-coupled receptors. In the CNS sphingosine-1-phosphate signaling in particular has emerged as a productive therapeutic target for the treatment of neurodegenerative disease, with the first small molecule targeting sphingosine-1-phosphate receptors approved roughly 15 years ago for the treatment of multiple sclerosis. As more specific activators and inhibitors of these receptors have been developed and entered the clinical trial pipeline it is an appropriate time to examine the current state of our knowledge of the role that these receptors play in the CNS and highlight the current landscape of available modulators targeting these pathways.