title: Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.
abstract: Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P(1) knock-out and the unavailability of selective agonists or antagonists. A potent, S1P(1)-receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5'-3-O-(thio)triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P(1)- but not S1P(3)-expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P(3) receptor reveals that agonism of S1P(1) receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P(1) receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P(3), and not S1P(1), is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor non-selective immunosuppressive agonists in wild-type mice is abolished in S1P(3)-/- mice, whereas S1P(1)-selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P(1) receptor agonists with an enhanced therapeutic window. S1P(1)-selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P(1) suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.
authors.affiliation: Department of Immunology, The Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: M Germana
authors.initials: MG
authors.lastname: Sanna
authors.forename: Jiayu
authors.initials: J
authors.lastname: Liao
authors.forename: Euijung
authors.initials: E
authors.lastname: Jo
authors.forename: Christopher
authors.initials: C
authors.lastname: Alfonso
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Ahn
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Peterson
authors.forename: Bill
authors.initials: B
authors.lastname: Webb
authors.forename: Sophie
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D006224:Cricetinae; D000068876:Fingolimod Hydrochloride; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008208:Lymphatic System / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology*; D008231:Lymphopenia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D049312:Receptors, Lysophospholipid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011494:Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium