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      Expression of lysophosphatidic acid receptors in the human lower esophageal sphincter

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          Abstract

          Lysophosphatidic acid (LPA) is a bioactive lipid that is involved in a variety of physiological and pathological processes occurring in the gastrointestinal tract. It acts via six distinct types of receptors, LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6, which belong to the family of G protein-coupled receptors. The aim of the present study was to detect the expression of the LPA receptors in the human lower esophageal sphincter (LES). Quantitative polymerase chain reaction and western blotting were used to analyze the expression of LPA1-6 receptors in sling and clasp fibers from the human LES. The results showed that the protein and mRNA expression levels of various LPA receptors were significantly different. Specifically, the mRNA and protein expression levels of the LPA1 receptor were higher compared with those of the other receptors. The prevalence of the LPA1 receptor mRNA and protein indicates that the LPA1 receptor is likely to be involved in the regulation of human LES functions.

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          The ins and outs of lysophosphatidic acid signaling.

          Wouter Moolenaar, Laurens van Meeteren, Ben Giepmans (2004)
          Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G-protein-coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved elusive. Excitingly, it has recently been discovered that LPA is generated from precursors by 'autotaxin', a once enigmatic exo-phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis.
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            GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5.

            Jerold Chun, Matthew E. Dubin, Richard Rivera … (2006)
            The signaling effects of lysophospholipids such as lysophosphatidic acid (LPA) are mediated by G protein-coupled receptors (GPCRs). There are currently four LPA receptors known as LPA(1-4). Genetic deletion studies have identified essential biological functions for LPA receptors in mice. However, these studies have also revealed phenotypes consistent with the existence of as yet unidentified receptors. Toward identifying new LPA receptors, we have screened collections of GPCR cDNAs using reverse transfection and cell-based assays. Here we report an interim result of one screen to identify receptors that produced LPA-dependent changes in cell shape: the orphan receptor GPR92 has properties of a new LPA receptor. Sequence analyses of human GPR92 and its mouse homolog have approximately 35% amino acid identity with LPA4/GPR23. The same cell-based approaches that were used to identify and/or characterize LPA(1-4), particularly heterologous expression in B103 cells or RH7777 cells, were utilized and compared with known LPA receptors. Retroviral-mediated expression of epitope-tagged receptors was further combined with G protein minigenes and pharmacological intervention, along with calcium imaging and whole-cell patch clamp electrophysiology. LPA-dependent receptor internalization following exposure to LPA but not related lysophospholipids was observed. Furthermore, LPA induced concentration-dependent activation of G(12/13) and G(q) and increased cAMP levels. Specific [3H]LPA binding was detected in cell membranes heterologously expressing GPR92 but not control membranes. Northern blot and reverse transcriptase-PCR studies indicated a broad low level of expression in many tissues including embryonic brain and enrichment in small intestine and sensory dorsal root ganglia, as well as embryonic stem cells. These results support GPR92 as a fifth LPA receptor, LPA5, which likely has distinct physiological functions in view of its expression pattern.
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              Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex

              J Chun, JA Weiner (1996)
              Neocortical neuroblast cell lines were used to clone G-protein-coupled receptor (GPCR) genes to study signaling mechanisms regulating cortical neurogenesis. One putative GPCR gene displayed an in situ expression pattern enriched in cortical neurogenic regions and was therefore named ventricular zone gene-1 (vzg-1). The vzg-1 cDNA hybridized to a 3.8-kb mRNA transcript and encoded a protein with a predicted molecular mass of 41-42 kD, confirmed by Western blot analysis. To assess its function, vzg-1 was overexpressed in a cell line from which it was cloned, inducing serum-dependent "cell rounding." Lysophosphatidic acid (LPA), a bioactive lipid present in high concentrations in serum, reproduced the effect seen with serum alone. Morphological responses to other related phospholipids or to thrombin, another agent that induces cell rounding through a GPCR, were not observed in vzg-1 overexpressing cells. Vzg-1 overexpression decreased the EC50 of both cell rounding and Gi activation in response to LPA. Pertussis toxin treatment inhibited vzg-1-dependent LPA-mediated Gi activation, but had no effect on cell rounding. Membrane binding studies indicated that vzg-1 overexpression increased specific LPA binding. These analyses identify the vzg-1 gene product as a receptor for LPA, suggesting the operation of LPA signaling mechanisms in cortical neurogenesis. Vzg-1 therefore provides a link between extracellular LPA and the activation of LPA- mediated signaling pathways through a single receptor and will allow new investigations into LPA signaling both in neural and nonneural systems.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Ther Med
                Journal ID (iso-abbrev): Exp Ther Med
                Journal ID (publisher-id): ETM
                Title: Experimental and Therapeutic Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-0981
                ISSN (Electronic): 1792-1015
                Publication date (Print): February 2014
                Publication date (Electronic): 06 December 2013
                Publication date PMC-release: 06 December 2013
                Volume: 7
                Issue: 2
                Pages: 423-428
                Affiliations
                Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
                Author notes
                Correspondence to: Professor Jun-Feng Liu, Department of Thoracic Surgery, Fourth Hospital, Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei 050011, P.R. China, E-mail: liujf1962@ 123456163.com
                Article
                Publisher ID: etm-07-02-0423
                DOI: 10.3892/etm.2013.1439
                PMC ID: 3881043
                PubMed ID: 24396418
                SO-VID: 1c98111b-9fe0-4e2f-8273-13a3c17de0c7
                Copyright © Copyright © 2014, Spandidos Publications
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 24 July 2013
                Date accepted : 29 November 2013
                Categories
                Subject: Articles

                ScienceOpen disciplines: Medicine
                Keywords: clasp fibers,sling fibers,human,lower esophageal sphincter,lysophosphatidic acid receptors
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: clasp fibers, sling fibers, human, lower esophageal sphincter, lysophosphatidic acid receptors

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