Figure 8: The role of S1P and its receptors in P-Selectin mobilization.
From: Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin
Schematic representation of the direct and indirect roles S1P plays in P-selectin mobilization. Mast cells release both histamine and S1P that can both mobilize P-selectin independently through the H1 and S1P3 receptor, respectively. However, histamine achieves full scale P-selectin mobilization by additional Gq-dependent activation of Sphk1, S1P production/release and subsequent activation of S1P3. Other P-selectin mobilizing agents such as epinephrine that require cAMP for P-selectin mobilization also employ Sphk1 for full-blown effect but do so through a Gs/AC/cAMP-dependent pathway. S1P1 plays an inhibitory effect on P-selectin-dependent rolling by reducing AC-induced Sphk1 activity through Gi. DOP and pFTY720 act in an inhibitory manner on rolling by downregulating S1P1 and S1P3, but in addition, pFTY720 directly inhibits the Gq-dependent part of S1P-incuded S1P3-dependent P-selectin mobilization. In summary, the pro-rolling effect of S1P3 dominates over the anti-rolling of S1P1, and the net effect of acute S1P exposure is an overall increase in P-selectin-dependent leukocyte rolling. AC, adenylate cyclase; AUY 954, S1P1-specific agonist; β2AR, β2 adrenergic receptor; DOP, the S1P lyase inhibitor 4-deoxypyridoxine; H1, H1 histamine receptor; PSGL, P-selectin glycoprotein ligand-1; Sphk1, sphingosine kinase 1; TY-52156, S1P3-specific inhibitor.
