A Loss-of-Function Polymorphism in the Human P2X4 Receptor Is Associated With Increased Pulse Pressure

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 P...

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Bibliographic Details
Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2011-12, Vol.58 (6), p.1086-1092
Main Authors: Stokes, Leanne, Scurrah, Katrina, Ellis, Justine A, Cromer, Brett A, Skarratt, Kristen K, Gu, Ben J, Harrap, Stephen B, Wiley, James S
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - analogs & derivatives
Adenosine Triphosphate - metabolism
Adenosine Triphosphate - pharmacology
Animals
Arterial hypertension. Arterial hypotension
Binding Sites
Biological and medical sciences
Blood and lymphatic vessels
Blood Pressure - genetics
Cardiology. Vascular system
Cell Line
Clinical manifestations. Epidemiology. Investigative techniques. Etiology
Dose-Response Relationship, Drug
Gene Frequency
Genotype
Humans
Medical sciences
Models, Molecular
New South Wales - epidemiology
Patch-Clamp Techniques
Polymorphism, Single Nucleotide
Protein Conformation
Protein Structure, Tertiary
Receptors, Purinergic P2X4 - chemistry
Receptors, Purinergic P2X4 - drug effects
Receptors, Purinergic P2X4 - genetics
Receptors, Purinergic P2X4 - physiology
Recombinant Fusion Proteins - physiology
Vascular Resistance - genetics
Zebrafish Proteins - chemistry
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Summary: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 μmol/L of ATP; n=4–8 cells; PCys 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% CI0.41–5.27). 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.
ISSN:0194-911X
1524-4563
DOI:10.1161/HYPERTENSIONAHA.111.176180