Sphingosine 1-phosphate SIP

RPK118 (Hayashi et aL, 2002). However, our understanding of the regulation of SIP synthesis remains incomplete at this time and is a major area of interest since it offers potential for the development of novel therapeutic agents, given the potential role of SIP in several major diseases (see Section E, below). 

Interestingly, the phenotype of the S1P, mouse is similar to that of platelet-derived growth factor B and platelet-derived growth factor Preceptor knockout mice, which also have impaired vascular maturation and die in utero. Moreover, crosstalk and signal integration between SIP, and platelet-derived growth factor P receptors appears to exist (see Section D.2). 

Alternatively, LPA could be produced by the action of PLA, followed by a lysophospholipase D. Several lysophospholipase D activities have been desCTibed, including intracellular forms that are either Mg -dependent (Wykle and Strum, 1991) or Mg -inhibited (Kawasaki and Snyder, 1987) and which hydrolyse alkylether-linked phosphatidylcholine (lyso-platelet-activating factor) but not the acyl class of lysophosphatidylchoUne. 

Finally, dephosphorylation of LPA to monoacylglycerol by lipid phosphate phosphatases can occur. 

Three LPA-specific G-protein coupled receptors have been cloned. Comparison of their amino acid sequences reveals approximately 50% identity, whereas the similarity between the LPA receptors and those for S1P is only around 34%. This indicates that the LPA receptors are a distinct receptor subfamily from that of SIP receptors, although the EDG nomenclature was originally applied to both (Fukushima et al, 2001 Chun et al., 2002). 

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G-protein-coupled receptors (GPCRs), although some of them additionally play a role in intracellular signal transduction. Sphingosine-1-phosphate (SIP) and... 

Sphingosine kinases (SphKs) catalyse the phosphorylation of sphingosine to sphingosine-1 -phosphate (SIP). 

Ishii I, Ye X, Friedman B, Kawamura S, Contos JJ, Kingsbury MA, Yang AH, Zhang G, Brown JH, Chun J (2002) Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (SIP) receptors, SlP(2)/LP(B2)/EDG-5 and SlP(3)/LP(B3)/EDG-3. J Biol Chem 277 25152-25159... 

Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H (2004) Sphingosine 1-phosphate (SIP) receptor subtypes SlPl and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279 13839-13848... 

Keywords Sphingosine 1-phosphate (SIP autoimmune diseases transplantation cancer cardiovascular diseases... 

Herr, D. R., Grillet, N., Schwander, M., Rivera, R., Muller, U., Chun, J. Sphingosine 1-phosphate (SIP) signaling is required for maintenance of hair cells mainly via activation of S1P2. J Neurosci 27 (2007) 1474-1478. 

Phosphate (Sphingosine 1-Phosphate, SIP Ceramide 1-Phosphate, CerIP) -Fatty acid (1-O-Acyt-Ceramide) -Phosphocholine (Sphingomelin)... 

In the search for bioactive sphingosine 1-phosphate (SIP) receptor ligands, a series of 2-amino-2-heterocyclic propanols (242-245) have been synthesized. These molecules were discovered as substrates of human sphingosine kinases (SPHKl and SPHK2). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the SI PI receptor. 

Figure 1. Metabolism of sphingosine 1-phosphate (SIP). ADP, adenosine 5 -diphosphate. ATP, adenosine 5 -triphosphate.

Figure 3. Receptor signalling by sphingosine 1-phosphate (SIP) and lysophosphatidic acid (LPA). G7 Gq/Gi2/i3, guanine nucleotide binding proteins. LPA, lysophosphatidic acid receptors. SIP, sphingosine 1-phosphate receptors.

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