Activation of nuclear receptors by prostaglandins

Center for Experimental Therapeutics, School of Medicine, University of Pennsylvania, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Thrombosis Research (Impact Factor: 2.45). 07/2003; 110(5-6):311-5. DOI: 10.1016/S0049-3848(03)00418-3
Source: PubMed


Deletion of membrane receptors for prostaglandins has revealed their importance in diverse biological systems. Some evidence has accrued to support the contention that they may also ligate nuclear receptors, particularly peroxisomal proliferator activator receptors (PPARs). This is most pronounced in the case of 15-deoxy PGJ2, a cyclopentanone derivative of PGJ2 as a ligand for PPARgamma. However, while this compound can ligate the PPAR, the quantities formed in vivo suggest that this is an unlikely endogenous ligand. Furthermore, biosynthesis is unaltered in murine atherosclerosis and other inflammatory and metabolic disorders where activation of this PPAR has been implicated. The suggestion that prostaglandins serve as endogenous ligands for nuclear receptors is presently configured on the use of synthetic compounds and immunoreactive quantitation of dubious validity. The application of quantitatively precise and sensitive physicochemical methodology will enhance experiments designed to address this hypothesis.

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    • "Later stages will promote non-enzymatic degradation of TxA 2 (half-life evaluated to 30s in physiological media) into the inactive and stable TxB 2 , and the predominance of PGD 2 and higher concentrations of PGE 2 will inhibit platelet aggregation. Moreover, PGE 2 is further chemically dehydrated into inactive PGA 2 (acidic conditions) or PGB 2 (basic conditions) [14], and PGD 2 into PGJ 2 , a mitogenic metabolite [15], and further into 15-deoxy- PGJ 2 , a peroxisome proliferating-activator receptor (PPAR) gamma ligand [16]. Although PGJ 2 and 15-dPGJ 2 have no defined biological activities in blood platelets, together with other metabolites such as TxB2, PGE 2 , PGD 2 , PGA 2 , PGB 2 , PGJ 2 , and 15-dPGJ 2 , they form mixtures of metabolites relating to platelet phenotypes at different times. "
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    • "Specific GPCRs have been identified for all the prostanoids, where there are at least nine known prostanoid receptor forms in mouse and man [47, 48]. Although most of the prostaglandin GPCRs are localised at the plasma membrane of platelets, vascular smooth muscle cells, and mast cells, some are situated at the nuclear envelope [49]. Four of these receptor subtypes bind PGE2 (EP1–EP4), two bind PGD2 (DP1 and DP2), and more specific receptors bind PGF2α, PGI2, and TXA2 (FP, IP, and TP, resp.) "
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