Lysophospholipid Receptors

Although historically considered as intermediates in the biosynthesis of glycerophospholipids and the degradation of sphingolipids, the lysophospholipids lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) together form a class of extracellular mediators that evoke a wide range of biological responses. LPA is generated extracellularly by the concerted action of several phospholipases on plasma lipids while S1P is generated by sphingosine kinases and released from cells by unknown mechanisms. LPA and S1P are both produced by thrombic stimulation of platelets and can accumulate in serum in low micromolar concentrations. In addition, LPA has been shown to accumulate in other body fluids under pathological conditions; for example, in the ascites of ovarian cancer patients.

Due to their high potency (EC50 1-100 nM) and their ability to elicit responses when applied extracellularly, as well as the sensitivity of many responses to pertussis toxin, it was proposed that both LPA and S1P mediated their effects via their interaction with G protein-coupled receptors (GPCRs). Thus, the identification of a set of LPA/S1P G protein-coupled receptors, referred to as the â Edgâ cluster (Endothelial differentiation gene), was a seminal event in understanding the biology of these mediators. As expected from consideration of other groups of GPCRs, the LPA receptors (LPA1, LPA2 and LPA3; formerly Edg-2, Edg-4 and Edg-7, respectively) are most similar to one another (55% identical amino acids). These receptors are strongly LPA-preferring and are not activated by S1P or phosphatidic acid (at concentrations up to 10 µM). Likewise, a variety of lysophospholipids with head groups have much lower potencies and efficacies.

The other five lysophospholipid receptors (S1P1-5; formerly Edg-1, Edg-5, Edg-3, Edg-6 and Edg-8, respectively) are S1P-preferring and are also most similar to one another (50% identical amino acids). Each of the S1P receptors has been subjected to binding analyses and the Kd values have been reported to be in the 2-60 nM range. Dihydro S1P (sphinganine 1-phosphate) is nearly equipotent with S1P, while addition of a choline head group (sphingosylphosphorylcholine; SPC) results in a molecule that, while active at the receptors, is distinctly less potent and less efficacious at all S1P receptor types. Phyto S1P is reported to be a high affinity ligand for the S1P4 receptor. Other sphingolipids and glycerol-based lysophospholipids (including LPA) are inactive at the S1P receptors at concentrations up to 10 µM.

The two fundamental strategies used to understand the biology/pathology associated with the LPA/S1P receptors are mouse genetics and chemical biology. Ablation of individual receptor genes in the germ lines of mice resulted in no obvious phenotype (S1P3, LPA2), reduced litter size (S1P2) with perinatal lethality and runting (LPA1), embryonic lethality (S1P1) or a defect of implantation (LPA3). The defect in the S1P1 receptor gene " knock-out" mice was due to failure of developing blood vessels to become invested with pericytes and smooth muscle cells when the S1P1 receptor was lacking in the endothelium. Mice with altered S1P4 or S1P5 receptor genes have not been reported. A zebrafish with a developmental cardiac defect has an underlying S1P receptor mutation, but the additional S1P receptor genes in fish (Takifugu rubripes has at least six) and evolutionary distance make a direct correlation to mammals impossible. Genetic analyses are hampered also by the apparent lack of LPA/S1P receptors in non-vertebrate animals.

The pro-motility, pro-mitogenic and anti-apoptotic responses to LPA and/or S1P have long fueled speculation that interference with their signaling via a small molecule receptor antagonist might be a useful anti-neoplastic strategy. However, this idea has yet to be reduced to practice in standard xenograft nude mouse models. Rather it was a S1P receptor agonist that proved most instructive. The lead compound is FTY720, which is a sphingosine analog that is being developed for use as an immune system modulator in organ transplant and autoimmune disease settings. FTY720 was found to be a pro-drug with phosphorylation by sphingosine kinase type 2 yielding the active molecule FTY720 phosphate (FTY720-P) that is a high affinity agonist at all S1P receptors except S1P2. Studies with FTY720-P and follow on S1P1 receptor agonists (e.g. SEW2871) have revealed a prominent role for S1P in lymphocyte trafficking. In a genetic correlate of this discovery, mice with the S1P1 receptor gene disrupted in the T lymphocyte lineage exhibit a profound defect in egress of thymocytes. The discovery of a S1P1/S1P3 antagonist series (VPC23019 is the lead compound) might provide tools useful in exploring a role in S1P receptor blockade in pathophysiologic settings.

The use of a combination of LPA, a LPA3 receptor agonist (OMPT) and a LPA1/LPA3 receptor antagonist (the precursor to VPC32183) has revealed that LPA3 antagonists are protective in a mouse model of acute renal injury. LPA, at low dosages, is also protective in this model, apparently by acting at the LPA1 receptor. It remains to be determined whether this finding will be confirmed with the aid of the appropriate genetic models.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Edg: Endothelial differentation gene
FTY720: 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol
JTE-013: 1-[1,3-Dimethyl-4-(2-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-4-(2,6-dichloro-4-pyridinyl)-semicarbazide
Ki16425: 3-(4-[4-([1-(2-Chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid
LPA: Lysophosphatidic acid
phytoS1P: phytoSphingosine 1-phosphate
SEW2871: 5-[4-Phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole
S1P: Sphingosine 1-phosphate
VPC23019: (R)-Phosphoric acid mono-[2-amino-2-(3-octyl-phenylcarbamoyl)-ethyl] ester
VPC32183: (S)-Phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl} ester

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