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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 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 Citation Map 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. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 2793-2800 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ib mechanoreceptor Mario Mazzucato, Paola Pradella, Maria Rita Cozzi, Luigi De Marco, and Zaverio M. Ruggeri From the Servizio Immunotrasfusionale e Analisi Cliniche, Centro di Riferimento Oncologico, Aviano, Italy; and the Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Departments of Molecular and Experimental Medicine and of Vascular Biology, Scripps Research Institute, La Jolla, CA. We 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 IIb3 activation. Fluid-dynamic conditions that are compatible with the existence of tensile stress on the bonds between glycoprotein Ib (GPIb) and the VWF A1 domain led to Ca++ release from intracellular stores (type / peaks), which preceded stationary platelet adhesion. Raised levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, as well as membrane-permeable calcium chelators, inhibited these [Ca++]i oscillations and prevented stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GPIb. Once adhesion was established through the integrin IIb3, new [Ca++]i oscillations (type ) of greater amplitude and duration, and involving a transmembrane ion flux, developed in association with the recruitment of additional platelets into aggregates. Degradation of released adenosine diphosphate (ADP) to AMP or inhibition of phosphatidylinositol 3-kinase (PI3-K) prevented this response without affecting stationary adhesion and blocked aggregation. These findings indicate that an initial signal induced by stressed GPIb-VWF bonds leads to IIb3 activation sufficient to support localized platelet adhesion. Then, additional signals from ADP receptors and possibly ligand-occupied IIb3, with the contribution of a pathway involving PI3-K, amplify platelet activation to the level required for aggregation. Our conclusions modify those proposed by others regarding the mechanisms that regulate signaling between GPIb and IIb3 and lead to platelet adhesion and aggregation on immobilized VWF. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. Labarque, K. Freson, C. Thys, C. Wittevrongel, M. F. Hoylaerts, R. De Vos, N. Goemans, and C. Van Geet Increased Gs signalling in platelets and impaired collagen activation, due to a defect in the dystrophin gene, result in increased blood loss during spinal surgery Hum. Mol. Genet., February 1, 2008; 17(3): 357 - 366. [Abstract] [Full Text] [PDF] S. P. Jackson The growing complexity of platelet aggregation Blood, June 15, 2007; 109(12): 5087 - 5095. [Abstract] [Full Text] [PDF] S. P. Kunapuli Response: Is there a physiologically relevant experimental model system to study GP1b-mediated signaling in platelets? 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