Members of the family of Lysophospholipid receptors are GPCRs (GPCR-A13) that are important for lipid signaling. Their endogenous ligands encompass lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The principal effects of LPA and S1P are growth related, including induction of cellular proliferation, alterations in differentiation and survival, and suppression of apoptosis. LPA and S1P also evoke cellular effector functions, which are dependent on cytoskeletal responses such as contraction, secretion, adhesion, and chemotaxis,. There are five S1PRs known to date, that activate different intracellular signaling pathways and differentially regulate endothelial cell function. S1PR1 couples to Gi and activates the phosphatidylinositol 3-kinase (PI3K) pathway, Rac, cortical actin assembly, and cell migration. In sharp contrast, S1PR2 antagonizes S1PR1-Gi-PI3K signaling in the endothelium through activation of the G12/13-Rho-Rho kinase (ROCK)-PTEN pathway. This implies that the balance between S1PR1 and S1PR2 signaling in a specific vascular bed will determine the endothelial responses to S1P.
The classical S1PR1 ligand Fingolimod (FTY 720, Axon 1485) is known for its characteristics as an immunomodulating drug, approved for treating multiple sclerosis. Interestingly, recent studies indicated the ligand could also be a candidate therapeutic drug for the treatment of heart failure and arrhythmias by activation of the P21-activated kinase-1 (Pak1).
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