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内容記述 |
Prostaglandin D2 (PGD2), an anti-inflammatory mediator, is acting through Gs-protein coupled D-type prostanoid (DP) receptors. DP receptors are not extensively distributed; in tissues, they are the least abundant among members of the prostanoid receptor family, whereas their primary ligand PGD2 is the main prostanoid in most tissues. PGD2 is dehydrated or isomerized to a number of metabolites enzymatically or nonenzymatically. To understand why many metabolites of PGD2 are produced via different pathways, regular cell-based experiments, Black/Leff operational model calculations, and in silico simulations were utilized. Here we show that, among the five metabolites of PGD2, prostaglandin J2 (PGJ2) was the most potent metabolite for DP receptors, particularly in the cAMP signaling pathway. This result was attributed to PGJ2 forming an extra and/or stronger hydrogen bond by more negatively charged carbonyl in the cyclopentene ring with DP receptors than PGD2. Therefore, when PGD2 is released into the blood, it would activate DP receptors, which are then continuously activated by PGJ2 to sustain the DP receptor/cAMP-mediated signaling pathway. Thus, the anti-inflammatory effects of PGD2 may be taken over/out competed and/or even enhanced by PGJ2. Here, PGJ2 was found to be a standout mediator of cAMP-mediated signaling pathway, which induces more potent and prolonged DP receptor activities as a biased ligand, possibly for resolving the inflammatory reaction. Moreover, since each metabolite showed different properties, these results provide insight into why many metabolites of PGD2 are produced and the miscellaneous physiological roles induced by the main prostanoid in most tissues through the least abundant DP receptors. |
