| A Loss-of-Function Polymorphism in the Human P2X4 Receptor Is Associated With Increased Pulse Pressure. | |
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MedLine Citation:
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PMID: 22068874 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response to shear stress and is, therefore, potentially relevant to arterial compliance and pulse pressure. Four identified nonsynonymous polymorphisms in P2RX4 were reproduced in recombinantly expressed human P2X4. Electrophysiological studies showed that one of these, the Tyr315>Cys mutation (rs28360472), significantly reduced the peak amplitude of the ATP-induced inward current to 10.9% of wild-type P2X4 receptors in transfected HEK-293 cells (10 μ mol/L of ATP; n=4-8 cells; P<0.001). Concentration-response curves for ATP and the partial agonist BzATP demonstrate that the 315Cys-P2X4 mutant had an increased EC(50) value for both ligands. Mutation of Tyr315>Cys likely disrupts the agonist binding site of P2X4 receptors, a finding supported by molecular modeling based on the zebrafish P2X4 receptor crystal structure. We tested inheritance of rs28360472 encoding the Tyr315>Cys mutation in P2RX4 against pulse pressure in 2874 subjects from the Victorian Family Heart Study. The minor allele frequency was 0.014 (1.4%). In a variance components analysis we found significant association with pulse pressure (P=0.023 for total association) where 1 minor allele increased pulse pressure by 2.84 mm Hg (95% CI: 0.41-5.27). This increase in pulse pressure associated with inheritance of 315Cys-P2X4 receptors might reflect reduced large arterial compliance as a result of impaired endothelium-dependent vasodilation in large arteries. |
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Authors:
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Leanne Stokes; Katrina Scurrah; Justine A Ellis; Brett A Cromer; Kristen K Skarratt; Ben J Gu; Stephen B Harrap; James S Wiley |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-7 |
Journal Detail:
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Title: Hypertension Volume: - ISSN: 1524-4563 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Penrith, New South Wales, Australia; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Florey Neurosciences Institute, and Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia; Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Health Innovations Research Institute and School of Medical Sciences, Royal Melbourne Institute of Technology University, Melbourne, Victoria, Australia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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