Agonist evoked increases in intraplatelet zinc couple to functional responses

Niaz, Ahmed and Taylor, Kirk and Lopes-Pires, Maria E. and Pugh, Nicholas (2019) Agonist evoked increases in intraplatelet zinc couple to functional responses. Thrombosis and Haemostasis, 119 (01). pp. 128-139. ISSN 0340-6245

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Official URL: http://dx.doi.org/10.1055/s-0038-1676589

Abstract

BACKGROUND:  Zinc (Zn2+) is an essential trace element that regulates intracellular processes in multiple cell types. While the role of Zn2+ as a platelet agonist is known, its secondary messenger activity in platelets has not been demonstrated. OBJECTIVES:  This article determines whether cytosolic Zn2+ concentrations ([Zn2+]i) change in platelets in response to agonist stimulation, in a manner consistent with a secondary messenger, and correlates the effects of [Zn2+]i changes on activation markers. METHODS:  Changes in [Zn2+]i were quantified in Fluozin-3 (Fz-3)-loaded washed, human platelets using fluorometry. Increases in [Zn2+]i were modelled using Zn2+-specific chelators and ionophores. The influence of [Zn2+]i on platelet function was assessed using platelet aggregometry, flow cytometry and Western blotting. RESULTS:  Increases of intra-platelet Fluozin-3 (Fz-3) fluorescence occurred in response to stimulation by cross-linked collagen-related peptide (CRP-XL) or U46619, consistent with a rise of [Zn2+]i. Fluoresence increases were blocked by Zn2+ chelators and modulators of the platelet redox state, and were distinct from agonist-evoked [Ca2+]i signals. Stimulation of platelets with the Zn2+ ionophores clioquinol (Cq) or pyrithione (Py) caused sustained increases of [Zn2+]i, resulting in myosin light chain phosphorylation, and cytoskeletal re-arrangements which were sensitive to cytochalasin-D treatment. Cq stimulation resulted in integrin αIIbβ3 activation and release of dense, but not α, granules. Furthermore, Zn2+-ionophores induced externalization of phosphatidylserine. CONCLUSION:  These data suggest that agonist-evoked fluctuations in intra-platelet Zn2+ couple to functional responses, in a manner that is consistent with a role as a secondary messenger. Increased intra-platelet Zn2+ regulates signalling processes, including shape change, αIIbβ3 up-regulation and dense granule release, in a redox-sensitive manner.

Item Type: Journal Article
Keywords: platelets, zinc, platelet activation, signal transduction, secretory vesicles, granule release
Faculty: Faculty of Science & Engineering
Depositing User: Ian Walker
Date Deposited: 07 Nov 2018 10:34
Last Modified: 14 Nov 2019 16:08
URI: http://arro.anglia.ac.uk/id/eprint/703804

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