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      Development of a Novel Transgenic Rat Overexpressing the P2Y 2 Nucleotide Receptor Using a Lentiviral Vector

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          Abstract

          The G protein-coupled P2Y<sub>2</sub> nucleotide receptor (P2Y<sub>2</sub>R) is upregulated in response to stress and tissue injury and has been postulated to play a role in chronic inflammation seen in atherosclerosis, Alzheimer’s disease and Sjögren’s syndrome. The role of P2Y<sub>2</sub>R upregulation in vivo is poorly understood, in part due to the lack of a P2Y<sub>2</sub>R overexpressing animal model. The P2Y<sub>2</sub>R overexpressing transgenic rat was generated using a lentiviral vector. Rats overexpressing P2Y<sub>2</sub>R showed a significant increase in P2Y<sub>2</sub>R mRNA levels in all tissues screened as compared to nontransgenic rats. Fura 2 imaging of smooth muscle cells (SMCs) isolated from aorta indicated that the percentage of cells exhibiting increases in the intracellular free calcium concentration in response to P2Y<sub>2</sub>R agonists was significantly greater in freshly isolated SMCs from transgenic rats than wild-type controls. Histopathological examination of tissues revealed that P2Y<sub>2</sub>R overexpressing rats develop lymphocytic infiltration in lacrimal glands and kidneys as early as at 3 months of age. These rats show similarities to patients with Sjögren’s syndrome who display lymphocyte-mediated tissue damage. This transgenic rat model of P2Y<sub>2</sub>R overexpression may prove useful for linking P2Y<sub>2</sub>R upregulation with chronic inflammatory diseases, neurodegenerative diseases and Sjögren’s syndrome.

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          Most cited references 42

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          International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy.

          There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor subtypes have been cloned and characterized and most orphan receptors de-orphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.
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            P2X receptors as cell-surface ATP sensors in health and disease.

            P2X receptors are membrane ion channels activated by the binding of extracellular adenosine triphosphate (ATP). For years their functional significance was consigned to distant regions of the autonomic nervous system, but recent work indicates several further key roles, such as afferent signalling, chronic pain, and in autocrine loops of endothelial and epithelial cells. P2X receptors have a molecular architecture distinct from other ion channel protein families, and have several unique functional properties.
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              ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors.

              Cells must amplify external signals to orient and migrate in chemotactic gradient fields. We find that human neutrophils release adenosine triphosphate (ATP) from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation by feedback through P2Y2 nucleotide receptors. Neutrophils rapidly hydrolyze released ATP to adenosine that then acts via A3-type adenosine receptors, which are recruited to the leading edge, to promote cell migration. Thus, ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2009
                August 2009
                21 January 2009
                : 46
                : 5
                : 447-458
                Affiliations
                aDepartment of Veterinary Pathobiology, College of Veterinary Medicine and bDepartment of Biochemistry, 540 Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Mo., and cNeuroscience Division, Department of Human Genetics, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Ga., USA
                Article
                194274 J Vasc Res 2009;46:447–458
                10.1159/000194274
                3593343
                19155635
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 2, References: 53, Pages: 12
                Categories
                Research Paper

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