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Platelets play a vital role in maintaining haemostasis. Human platelet activation depends on Ca 2+ release, leading to cell activation, granule secretion and aggregation. NAADP (nicotinic acid-adenine dinucleotide phosphate) is a Ca 2+ -releasing second messenger that acts on acidic Ca 2+ stores and is used by a number of mammalian systems. In human platelets, NAADP has been shown to release Ca 2+ in permeabilized human platelets and contribute to thrombin-mediated platelet activation. In the present study, we have further characterized NAADP-mediated Ca 2+ release in human platelets in response to both thrombin and the GPVI (glycoprotein VI)-specific agonist CRP (collagen-related peptide). Using a radioligand-binding assay, we reveal an NAADP-binding site in human platelets, indicative of a platelet NAADP receptor. We also found that NAADP releases loaded 45 Ca 2+ from intracellular stores and that total platelet Ca 2+ release is inhibited by the proton ionophore nigericin. Ned-19, a novel cell-permeant NAADP receptor antagonist, competes for the NAADP-binding site in platelets and can inhibit both thrombin- and CRP-induced Ca 2+ release in human platelets. Ned-19 has an inhibitory effect on platelet aggregation, secretion and spreading. In addition, Ned-19 extends the clotting time in whole-blood samples. We conclude that NAADP plays an important role in human platelet function. Furthermore, the development of Ned-19 as an NAADP receptor antagonist provides a potential avenue for platelet-targeted therapy and the regulation of thrombosis. © The Authors Journal compilation © 2012 Biochemical Society.

Original publication

DOI

10.1042/BJ20111175

Type

Journal article

Journal

Biochemical Journal

Publication Date

01/01/2012

Volume

441

Pages

435 - 442