Lysophospholipid (S1P) receptors


Sphingosine 1-phosphate (S1P) receptors are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [1,2], the receptors are currently designated as S1P1R through S1P5R [3,1,2]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors have been knocked-out in mice constitutively and in some cases, conditionally.

S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [4,5]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems.

Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [6,7]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [8,9]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [10]. siponimod and ozanimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [1,2]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [11,12,13,14].


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  2. Mizuno H, Kihara Y. Druggable Lipid GPCRs: Past, Present, and Prospects. Adv Exp Med Biol 2020;1274:223-258.
  3. Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J Biol Chem 1990;265:9308-13.
  4. Blaho VA, Galvani S, Engelbrecht E, et al. HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 2015;523:342-6.
  5. Galvani S, Sanson M, Blaho VA, et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal 2015;8:ra79.
  6. Kono M, Conlon EG, Lux SY, et al. Bioluminescence imaging of G protein-coupled receptor activation in living mice. Nat Commun 2017;8:1163.
  7. Kono M, Tucker AE, Tran J, et al. Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J Clin Invest 2014;124:2076-86.
  8. Hanson MA, Roth CB, Jo E, et al. Crystal structure of a lipid G protein-coupled receptor. Science 2012;335:851-5.
  9. Blaho VA, Chun J. 'Crystal' Clear? Lysophospholipid Receptor Structure Insights and Controversies. Trends Pharmacol Sci 2018;39:953-966.
  10. Chun J, Kihara Y, Jonnalagadda D, et al. Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders. Annu Rev Pharmacol Toxicol 2019;59:149-170.
  11. Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 2015;125:1379-87.
  12. Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol 2011;69:759-77.
  13. Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci 2013;328:9-18.
  14. Groves A, Kihara Y, Jonnalagadda D, et al. A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes). eNeuro 2018;5:.
Excerpt from IUPHAR/BPS Guide to Pharmacology