title: Intracrine signaling through lipid mediators and their cognate nuclear G-protein-coupled receptors: a paradigm based on PGE2, PAF, and LPA1 receptors.
abstract: Prostaglandins (PGs), platelet-activating factor (PAF), and lysophosphatidic acid (LPA) are ubiquitous lipid mediators that play important roles in inflammation, cardiovascular homeostasis, and immunity and are also known to modulate gene expression of specific pro-inflammatory genes. The mechanism of action of these lipids is thought to be primarily dependent on their specific plasma membrane receptors belonging to the superfamily of G-protein-coupled receptors (GPCR). Increasing evidence suggests the existence of a functional intracellular GPCR population. It has been proposed that immediate effects are mediated via cell surface receptors whereas long-term responses are dependent upon intracellular receptor effects. Indeed, receptors for PAF, LPA, and PGE(2) (specifically EP(1), EP(3), and EP(4)) localize at the cell nucleus of cerebral microvascular endothelial cells of newborn pigs, rat hepatocytes, and cells overexpressing each receptor. Stimulation of isolated nuclei with these lipids reveals biological functions including transcriptional regulation of major genes, namely c-fos, cylooxygenase-2, and endothelial as well as inducible nitric oxide synthase. In the present review, we shall focus on the nuclear localization and signaling of GPCRs recognizing PGE(2), PAF, and LPA phospholipids as ligands. Mechanisms on how nuclear PGE2, PAF, and LPA receptors activate gene transcription and nuclear localization pathways are presented. Intracrine signaling for lipid mediators uncover novel pathways to elicit their effects; accordingly, intracellular GPCRs constitute a distinctive mode of action for gene regulation.
authors.affiliation: Department of Pediatrics, Research Center of Hôpital Sainte-Justine, Université de Montréal, QC, Canada.
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Tello
authors.forename: Martin
authors.initials: M
authors.lastname: Leduc
authors.forename: Lenka
authors.initials: L
authors.lastname: Rihakova
authors.forename: Michela
authors.initials: M
authors.lastname: Bossolasco
authors.forename: Ghassan
authors.initials: G
authors.lastname: Bkaily
authors.forename: Krishna
authors.initials: K
authors.lastname: Peri
authors.forename: Daya R
authors.initials: DR
authors.lastname: Varma
authors.forename: Robert
authors.initials: R
authors.lastname: Orvoine
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008246:Lysophospholipids; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D018078:Receptors, Prostaglandin E; C039351:platelet activating factor receptor; D015232:Dinoprostone; C032881:lysophosphatidic acid