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 (S1P) as a critical regulator of cell growth and death has stimulated increasing research effort to clarify the role of ceramide and S1P in various diseases associated with dysregulated cell proliferation and apoptosis. S1P acts mainly, but not exclusively, by binding to and activating specific cell surface receptors, the so-called S1P 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 S1P action. Whereas classical receptor antagonists will directly block S1P action, S1P 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 S1P receptors, but upon prolonged presence, it displays antagonistic activity by specifically desensitizing the S1P(1) receptor subtype. This commentary will cover the most recent developments in the field of S1P receptor pharmacology and highlights the potential therapeutic benefit that can be expected from these novel drug targets in the future.
Huwiler
Andrea
A
Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. Huwiler@pki.unibe.ch
Pfeilschifter
Josef
J
D000818:Animals; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D010069:Oxadiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D013438:Sulfhydryl Compounds; D053778:Thiazolidines; D013876:Thiophenes; D000099157:Sphingosine Kinase; C515031:BML 241; C471998:JTE 013; C501899:KRP-203; C503964:SEW2871; C060506:sphingosine 1-phosphate