Targeting sphingosine-1-phosphate signaling in lung diseases.
Sphingosine-1-phosphate (S1P), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phosphatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL). As a ligand for specific G-protein-coupled receptors, S1P1-5, which are differentially expressed in different cell types, S1P generates downstream signals that play crucial role in developmental and disease related pathologies. In addition to acting extracellularly on receptors located on the plasma membrane, S1P can also act intracellularly, independently of S1P1-5, affecting calcium homeostasis and cell proliferation. The SphKs /S1P /S1PL metabolic pathway is implicated in numerous human pathologies including respiratory disorders, thereby raising the possibility that manipulating intracellular S1P levels could offer therapeutic potential in ameliorating lung diseases. This review focuses on the prospects of targeting S1P signaling and S1P metabolizing enzymes using small molecule inhibitors, receptor agonists, and antagonists in the treatment of lung diseases.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, IL, USA.
David L
DL
Ebenezer
Department of Pharmacology, University of Illinois at Chicago, IL, USA.
Panfeng
P
Fu
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, IL, USA; Department of Bioengineering, University of Illinois at Chicago, IL, USA. Electronic address: visnatar@uic.edu.
Viswanathan
V
Natarajan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008171:Lung Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008246:Lysophospholipids / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
D000255:Adenosine Triphosphate; D008024:Ligands; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
Lung diseases; S1P receptor; Sphingosine kinase; Sphingosine-1-phosphate; Sphingosine-1-phosphate lyase; Sphingosine-1-phosphate phosphatase