Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate (2004)

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 S1P1 knock-out and the unavailability of selective agonists or antagonists. A potent, S1P1-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 S1P1- but not S1P3-expressing cells agonist lymphocyte of selective with receptor of S1P1 receptor is to lymphocyte S1P1 receptor agonist associated with and of and not is bradycardia. by S1P receptor non-selective agonists is agonist not bradycardia. of receptor of lymphocyte recirculation and heart the of selective S1P1 receptor agonists with agonists of and and the of the S1P1 selective the of receptor 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 S1P1 knock-out and the unavailability of selective agonists or antagonists. A potent, S1P1-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 S1P1- but not S1P3-expressing cells agonist lymphocyte of selective with receptor of S1P1 receptor is to lymphocyte S1P1 receptor agonist associated with and of and not is bradycardia. by S1P receptor non-selective agonists is agonist not bradycardia. of receptor of lymphocyte recirculation and heart the of selective S1P1 receptor agonists with agonists of and and the of the S1P1 selective the of receptor Sphingosine 1-phosphate S1P, guanosine of S1P, guanosine of through high affinity G-protein-coupled is with multiple heart coronary artery endothelial and has been to the recirculation of of the the including of endothelial and of and lymphocyte recirculation of S1P by to and high to the of S1P receptor high of and coronary artery of S1P, through of the of by the the to S1P, by receptor the of the receptor and signals and to the contribution of individual receptors has been limited by the unavailability of selective agonists or antagonists. and of the S1P1 is embryonic to the of of receptor receptor the has selective S1P receptor of the of of the recirculation of of and the high and to to the and S1P receptors the lymphocyte non-selective S1P receptor agonists and but not the of the by the of Inhibition of lymphocyte is associated with immunosuppression and is and transient S1P receptor agonists the of receptors with with the of S1P receptor to receptor of the of the S1P1 and S1P1 is of lymphocyte was by of agonists receptor and and the of selective S1P receptor agonists is selective signals was the of was and cells S1P receptors and by cells or and and and with and of of S1P or to of and of the was by of to the and calcium was was by and to S1P of with by to and and and calcium to or S1P or is of of 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