Nuclear prostaglandin receptors: role in pregnancy and parturition?

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Abstract

The key regulatory role of prostanoids [prostaglandins (PGs) and thromboxanes (TXs)] in the maintenance of pregnancy and initiation of parturition has been established [1], [2], [3]. However, our understanding of how these events are fine-tuned by the recruitment of specific signaling pathways remains unclear. Whereas, initial thoughts were that PGs were lipophilic and would easily cross cell membranes without specific receptors or transport processes, it has since been realized that PG signaling occurs via specific cell surface G-protein coupled receptors (GPCRs) coupled to classical adenylate cyclase or inositol phosphate signaling pathways. Furthermore, specific PG transporters have been identified and cloned [4], [5], [6], [7] adding a further level of complexity to the regulation of paracrine action of these potent bioactive molecules. It is now apparent that PGs also activate nuclear receptors, opening the possibility of novel intracrine signaling mechanisms. The existence of intracrine signaling pathways is further supported by accumulating evidence linking the perinuclear localization of PG synthesizing enzymes with intracellular PG synthesis. This review will focus on the evidence for a role of nuclear actions of PGs in the regulation of 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.

References (229)

  • L.L Lin et al.

    cPLA2 is phosphorylated and activated by MAP kinase

    Cell

    (1993)
  • A.M Sheridan et al.

    Nuclear translocation of cytosolic phospholipase A2 is induced by ATP depletion

    J. Biol. Chem.

    (2001)
  • A.M Capriotti et al.

    Arachidonate released upon agonist stimulation preferentially originates from arachidonate most recently incorporated into nuclear membrane phospholipids

    J. Biol. Chem.

    (1988)
  • M.K Regier et al.

    Localization of prostaglandin endoperoxide synthase-1 to the endoplasmic reticulum and nuclear envelope is independent of its C-terminal tetrapeptide-PTEL

    Arch. Biochem. Biophys.

    (1995)
  • I Morita et al.

    Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2

    J. Biol. Chem.

    (1995)
  • A.G Spencer et al.

    Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy

    J. Biol. Chem.

    (1998)
  • K.W Marvin et al.

    Subcellular localization of prostaglandin H synthase-2 in a human amnion cell lineimplications for nuclear localized prostaglandin signaling pathways

    Prostagl. Leukot. Essent. Fatty Acids

    (2000)
  • N Ueno et al.

    Coupling between cyclooxygenase, terminal prostanoid synthase, and phospholipase A2

    J. Biol. Chem.

    (2001)
  • X.S Chen et al.

    cDNA cloning, expression, mutagenesis, intracellular localization, and gene chromosomal assignment of mouse 5-lipoxygenase

    J. Biol. Chem.

    (1995)
  • X.S Chen et al.

    Determinants of 5-lipoxygenase nuclear localization using green fluorescent protein/5-lipoxygenase fusion proteins

    J. Biol. Chem.

    (1998)
  • P Christmas et al.

    Differential localization of 5- and 15-lipoxygenases to the nuclear envelope in RAW macrophages

    J. Biol. Chem.

    (1999)
  • A.M Healy et al.

    Identification of a bipartite nuclear localization sequence necessary for nuclear import of 5-lipoxygenase

    J. Biol. Chem.

    (1999)
  • S.M Jones et al.

    Structural and functional criteria reveal a new nuclear import sequence on the 5-lipoxygenase protein

    J. Biol. Chem.

    (2002)
  • T.G Brock et al.

    Co-localization of leukotriene A4 hydrolase with 5-lipoxygenase in nuclei of alveolar macrophages and rat basophilic leukemia cells but not neutrophils

    J. Biol. Chem.

    (2001)
  • T Tanioka et al.

    Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis

    J. Biol. Chem.

    (2000)
  • M Murakami et al.

    Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2

    J. Biol. Chem.

    (2000)
  • M Murakami et al.

    Prostaglandin E synthase

    Prostagl. Other Lipid Mediat.

    (2002)
  • Y Urade et al.

    Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase

    Biochim. Biophys. Acta

    (2000)
  • K Ohno et al.

    Characterization of the transport system of prostaglandin A2 in L-1210 murine leukemia cells

    Biochem. Pharmacol.

    (1993)
  • K Matsumoto et al.

    Arachidonic acid metabolism by nuclei of a retinoic acid—or vitamin D3—differentiated human leukemia cell line HL-60

    Prostagl. Leukot. Essent. Fatty Acids

    (1994)
  • M Bhattacharya et al.

    Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear envelope

    J. Biol. Chem.

    (1999)
  • P.H Watson et al.

    Nuclear localization of the type 1 parathyroid hormone/parathyroid hormone-related peptide receptor in MC3T3-E1 cellsassociation with serum-induced cell proliferation

    Bone

    (2000)
  • L Hunyady et al.

    Mechanisms and functions of AT(1) angiotensin receptor internalization

    Regul. Pept.

    (2000)
  • K Seta et al.

    AT1 receptor mutant lacking heterotrimeric G protein coupling activates the Src-Ras-ERK pathway without nuclear translocation of ERKs

    J. Biol. Chem

    (2002)
  • G Innamorati et al.

    The long and the short cycle. Alternative intracellular routes for trafficking of G-protein-coupled receptors

    J. Biol. Chem.

    (2001)
  • B Pollok-Kopp et al.

    Analysis of ligand-stimulated CC chemokine receptor 5 (CCR5) phosphorylation in intact cells using phosphosite-specific antibodies

    J. Biol. Chem.

    (2003)
  • X Zhang et al.

    PPAR and immune system—what do we know?

    Int. Immunopharmacol.

    (2002)
  • J Vamecq et al.

    Medical significance of peroxisome proliferator-activated receptors

    Lancet

    (1999)
  • R Mukherjee et al.

    Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists

    J. Biol. Chem.

    (1997)
  • G Xing et al.

    Rat PPAR delta contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei

    Biochem. Biophys. Res. Commun.

    (1995)
  • E.Z Amri et al.

    Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors

    J. Biol. Chem.

    (1995)
  • R.F Morrison et al.

    Hormonal signaling and transcriptional control of adipocyte differentiation

    J. Nutr.

    (2000)
  • J.A Keelan et al.

    The molecular mechanisms of term and preterm laborrecent progress and clinical implications

    Clin. Obstet. Gynecol.

    (1997)
  • M.L Pucci et al.

    Cloning of mouse prostaglandin transporter PGT cDNAspecies-specific substrate affinities

    Am. J. Physiol.

    (1999)
  • N Kanai et al.

    Identification and characterization of a prostaglandin transporter

    Science

    (1995)
  • R Lu et al.

    Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT)

    J. Clin. Invest.

    (1996)
  • S Narumiya et al.

    Genetic and pharmacological analysis of prostanoid receptor function

    J. Clin. Invest.

    (2001)
  • D.M Slater et al.

    Prostaglandins and prostanoid receptors in human pregnancy and parturition

    J. Soc. Gynecol. Invest.

    (2002)
  • V.L Schuster

    Molecular mechanisms of prostaglandin transport

    Annu. Rev. Physiol.

    (1998)
  • S Endo et al.

    Expression of PGT in MDCK cell monolayerspolarized apical localization and induction of active PG transport

    Am. J. Physiol. Renal Physiol.

    (2002)
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