New players on the center stage: Sphingosine 1-phosphate and its receptors as drug targets

The recent identification of a cellular balance between ceramide and sphingosine 1-phosphate (SIP) as a critical regulator of cell growth and death has stimulated increasing research effort to clarify the role of ceramide and SIP in various diseases associated with dysregulated cell proliferation and apoptosis. SIP acts mainly, but not exclusively, by binding to and activating specific cell surface receptors, the so-called SIP receptors. These receptors belong to the class of G protein-coupled receptors that constitute five subtypes, denoted as S1P(1)-S1P(5), and represent attractive pharmacological targets to interfere with SIP action. Whereas classical receptor antagonists will directly block SIP action, SIP receptor agonists have also proven useful, as recently shown for the sphingolipid-like immunomodulatory substance FTY720. When phosphorylated by sphingosine kinase to yield FTY720 phosphate, it acutely acts as an agonist at SIP receptors, but upon prolonged presence, it displays antagonistic activity by specifically desensitizing the SIP, receptor subtype. This commentary will cover the most recent developments in the field of SIP receptor pharmacology and highlights the potential therapeutic benefit that can be expected from these novel drug targets in the future. (C) 2008 Elsevier Inc. All rights reserved.