Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/15682
Title: Primary and secondary agonists can use P2X receptors as a major pathway to increase intracellular Ca in the human platelet
Authors: Fung, C. Y. E.
Cendana, C.
Mahaut-smith, Martin P.
Farndale, R. W.
First Published: May-2007
Publisher: Wiley
Citation: Journal of Thrombosis and Haemostasis, 2007, 5 (5), pp. 910-917
Abstract: In the platelet, it is well established that many G-protein- and tyrosine kinase-coupled receptors stimulate phospholipase-C-dependent Ca[superscript: 2+] mobilization; however, the extent to which secondary activation of adenosine 5′-triphosphate (ATP)-gated P2X[subscript: 1] receptors contributes to intracellular Ca[superscript: 2+] responses remains unclear. We now show that selective inhibition of P2X1 receptors substantially reduces the [Ca[superscript: 2+]]i increase evoked by several important agonists in human platelets; for collagen, thromboxane A2, thrombin, and adenosine 5′-diphoshate (ADP) the maximal effect was a reduction to 18%, 34%, 52%, and 69% of control, respectively. The direct contribution of P2X[subscript: 1] to the secondary Ca[superscript: 2+] response was far greater than that of either P2Y receptors activated by co-released ADP, or via synergistic P2X[subscript: 1]:P2Y interactions. The relative contribution of P2X[subscript: 1] to the peak Ca[superscript: 2+] increase varied with the strength of the initial stimulus, being greater at low compared to high levels of stimulation for both glycoprotein VI and PAR-1, whereas P2X[subscript: 1] contributed equally at both low and high levels of stimulation of thromboxane A2 receptors. In contrast, only strong stimulation of P2Y receptors resulted in significant P2X[subscript: 1] receptor activation. ATP release was detected by soluble luciferin:luciferase in response to all agonists that stimulated secondary P2X[subscript: 1] receptor activation. However, P2X[subscript: 1] receptors were stimulated earlier and to a greater extent than predicted from the average ATP release, which can be accounted for by a predominantly autocrine mechanism of activation. Given the central role of [Ca[superscript: 2+]]i increases in platelet activation, these studies indicate that ATP should be considered alongside ADP and thromboxane A[subscript: 2] as a significant secondary platelet agonist.
DOI Link: 10.1111/j.1538-7836.2007.02525.x
ISSN: 1538-7933
eISSN: 1538-7836
Links: http://hdl.handle.net/2381/15682
http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2007.02525.x/abstract
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2007 The Authors. Journal Compilation © 2007 International Society on Thrombosis and Haemostasis. Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology



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