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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0514. This Article Full Text (PDF) All Versions of this Article: 2002-02-0514v1 100/8/2793    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mazzucato, M. Articles by Ruggeri, Z. M Search for Related Content PubMed PubMed Citation Articles by Mazzucato, M. Articles by Ruggeri, Z. M Social Bookmarking                   What's this? Submitted February 19, 2002 Accepted May 21, 2002 Sequential cytoplasmic calcium signals in a two-stage platelet activation process induced by the glycoprotein Ib mechanoreceptor Mario Mazzucato, Paola Pradella, Maria Rita Cozzi, Luigi De Marco, and Zaverio M Ruggeri* Servizio Immunotrasfusionale, Centro di Riferimento Oncologico, Aviano, Pordenone, Italy Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: ruggeri{at}scripps.edu. We have found that the interaction of platelets with immobilized von Willebrand factor (VWF) under flow induces distinct elevations of cytosolic Ca++ concentration ([Ca++]i) that are associated with sequential stages of integrin IIbß3 activation. Fluid dynamic conditions that are compatible with the existence of tensile stress on the bonds between glycoprotein (GP) Ib and the VWF A1 domain lead to Ca++ release from intracellular stores (type /ß peaks), which precedes stationary platelet adhesion. Raised cAMP/cGMP levels, as well as membrane permeable calcium chelators, inhibit these [Ca++]i oscillations and prevent stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GP Ib. Once adhesion is established through the integrin IIbß3 , new [Ca++]i oscillations (type ) of greater amplitude and duration, and involving a transmembrane ion flux, develop in association with the recruitment of additional platelets into aggregates. Degradation of released ADP to AMP or inhibition of phosphatidylinositol 3-kinase prevent this response without affecting stationary adhesion, and block aggregation. These findings indicate that an initial signal induced by stressed GP Ib-VWF bonds leads to IIbß3 activation sufficient to support localized platelet adhesion. Then, additional signals from ADP receptors and, possibly, ligand-occupied IIbß3, with the contribution of a pathway involving phosphatidylinositol 3-kinase, amplify platelet activation to the level required for aggregation. Our conclusions modify concepts proposed by others on the mechanisms that regulate signaling between GP Ib and IIbß3 and lead to platelet adhesion and aggregation on immobilized VWF. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. A. Schmaier and M. L. Kahn Platelet integrin signaling: wherefore art thou? Blood, September 24, 2009; 114(13): 2571 - 2572. [Full Text] [PDF] M. Mazzucato, M. R. Cozzi, M. Battiston, M. Jandrot-Perrus, M. Mongiat, P. Marchese, T. J. Kunicki, Z. M. Ruggeri, and L. 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