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ATP Augments von Willebrand Factor-dependent Shear-induced Platelet Aggregation through Ca2+-Calmodulin and Myosin Light Chain Kinase Activation*

C. Oury,E. Sticker,H. Cornelissen,R. De vos,J. Vermylen,M. Hoylaerts

Published 2004 in Journal of Biological Chemistry

ABSTRACT

Shear stress triggers von Willebrand factor (VWF) binding to platelet glycoprotein Ibα and subsequent integrin αIIbβ3-dependent platelet aggregation. Concomitantly, nucleotides are released from plateletdense granules, and ADP is known to contribute to shear-induced platelet aggregation (SIPA). We found that the impaired SIPA of platelets from a Hermansky-Pudlak patient lacking dense granules was restored by exogenous l-β,γ-methylene ATP, a stable P2X1 agonist, as well as by ADP, confirming that in addition to ADP (via P2Y1 and P2Y12), ATP (via P2X1) also contributes to SIPA. Likewise, SIPA of apyrase-treated platelets was restored upon P2X1 activation with l-β,γ-methylene ATP, which promoted granule centralization within platelets and stimulated P-selectin expression, which is a marker of α-granule release. In addition, during SIPA, platelet degranulation required both extracellular Ca2+ and VWF-glycoprotein Ibα interactions without involving αIIbβ3. Neither platelet release nor SIPA was affected by protein kinase C inactivation, even though protein kinase C blockade inhibits platelet responses to collagen and thrombin in stirring conditions. In contrast, inhibiting myosin light chain (MLC) kinase with ML-7 reduced platelet release and SIPA by 30%. Accordingly, the potentiating effect of P2X1 stimulation on the aggregation of apyrase-treated platelets coincided with intensified phosphorylation of MLC and was abrogated by ML-7. SIPA-induced MLC phosphorylation occurred exclusively through released nucleotides and selective antagonism of P2X1 with MRS2159-reduced SIPA, ATP release, and potently inhibited MLC phosphorylation. We conclude that the P2X1 ion channel induces MLC-mediated cytoskeletal rearrangements, thus contributing to SIPA and degranulation during VWF-triggered platelet activation.

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