Prostaglandins, Leukotrienes and Essential Fatty Acids
Nuclear prostaglandin receptors: role in pregnancy and parturition?
Section snippets
Paracrine/autocrine versus intracrine PG signaling
Prostanoids are synthesized from arachidonic acid by the action of cyclooxygenase (COX)-1 or -2 (also called PGH synthase or PG endoperoxide synthase) and specific PG isomerases/synthases [8], [9]. It is thought that PGs, upon synthesis, rapidly diffuse across the plasma membrane to act on neighboring cells. Although, experimental evidence is scarce, a recent study has demonstrated that the efflux of [3H]-PGE2 from microinjected Xenopus oocytes is indeed consistent with simple diffusion [4],
G-protein coupled receptors
Intriguing new research has revealed a novel nuclear localization of PG receptors, which were previously thought to be localized to the plasma membrane [62], [63], [64], [65]. Initially, radioligand binding studies revealed specific binding of PGE2 to nuclear fractions of newborn pig brain and adult pig myometrium, while specific binding of PGD2 was observed in nuclear fractions from brain [62]. Immunolabeling, using a specific anti-EP1 subtype antibody, confirmed a perinuclear localization of
PPAR ligands
The first member of the PPAR family to be cloned (PPARα) was identified as a transcription factor, activated by a diverse class of hepatocarcinogens that cause proliferation of peroxisomes [108]. Since that time, considerable effort has been directed towards the identification of endogenous and synthetic ligands. A variety of different PPAR ligands have been discovered. These include a number of natural compounds such as fatty acids and eicosanoids, hypolipidemic agents and the
PPARs in pregnancy and parturition
Investigation of the expression and function of PPARs in pregnancy and in gestational tissues in particular has focused mainly on PPARγ. Evidence for a key role of PPARδ in pregnancy is accumulating, but surprisingly little information exists regarding the function of PPARα in these tissues. Key findings are summarized below.
Conclusions
It is clear that a complex series of pathways are involved in the generation of PG signaling events. Fine-tuning of these pathways, and thus the final biological response, may be regulated at a number of different levels. For example by (1) the regulation of expression level or activity of PG biosynthetic enzymes (phospholipases, COXs and specific PG synthases); (2) subcellular compartmentalization of these enzymes for functional activity; (3) the regulated transport of PGs to intracellular or
Acknowledgements
Funding was provided by The Health Research Council of New Zealand, Royal Society of New Zealand Marsden Fund, New Zealand Lottery Health Grants Board, Auckland Medical Research Foundation and the University of Auckland Research Council.
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