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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4069-4079. Prepublished online as a Blood First Edition Paper on July 2, 2008; DOI 10.1182/blood-2008-05-157883. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-05-157883v1 112/10/4069    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Purvis, J. E. Articles by Diamond, S. L. Search for Related Content PubMed PubMed Citation Articles by Purvis, J. E. Articles by Diamond, S. L. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A molecular signaling model of platelet phosphoinositide and calcium regulation during homeostasis and P2Y1 activation Jeremy E. Purvis1,2, Manash S. Chatterjee1,3, Lawrence F. Brass4, and Scott L. Diamond1,3 1 Institute for Medicine and Engineering, 2 Center for Bioinformatics, 3 Department of Chemical and Biomolecular Engineering, and 4 Department of Medicine, University of Pennsylvania, Philadelphia To quantify how various molecular mechanisms are integrated to maintain platelet homeostasis and allow responsiveness to adenosine diphosphate (ADP), we developed a computational model of the human platelet. Existing kinetic information for 77 reactions, 132 fixed kinetic rate constants, and 70 species was combined with electrochemical calculations, measurements of platelet ultrastructure, novel experimental results, and published single-cell data. The model accurately predicted: (1) steady-state resting concentrations for intracellular calcium, inositol 1,4,5-trisphosphate, diacylglycerol, phosphatidic acid, phosphatidylinositol, phosphatidylinositol phosphate, and phosphatidylinositol 4,5-bisphosphate; (2) transient increases in intracellular calcium, inositol 1,4,5-trisphosphate, and Gq-GTP in response to ADP; and (3) the volume of the platelet dense tubular system. A more stringent test of the model involved stochastic simulation of individual platelets, which display an asynchronous calcium spiking behavior in response to ADP. Simulations accurately reproduced the broad frequency distribution of measured spiking events and demonstrated that asynchronous spiking was a consequence of stochastic fluctuations resulting from the small volume of the platelet. The model also provided insights into possible mechanisms of negative-feedback signaling, the relative potency of platelet agonists, and cell-to-cell variation across platelet populations. This integrative approach to platelet biology offers a novel and complementary strategy to traditional reductionist methods. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Systems biology meets platelet biology Michael C. Berndt and Robert K. Andrews Blood 2008 112: 3920-3921. [Full Text] [PDF]

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