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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-10-3080. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3080v1 101/12/4828    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 Patel, Y. M. Articles by Savidge, G. Search for Related Content PubMed PubMed Citation Articles by Patel, Y. M. Articles by Savidge, G. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4828-4835 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Evidence for a role for Gi1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Gi1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder Yatin M. Patel, Kirti Patel, Salman Rahman, Mark P. Smith, Gillian Spooner, Rushika Sumathipala, Michael Mitchell, Geraldine Flynn, Alexandra Aitken, and Geoffrey Savidge From the Department of Haematology, Canterbury Health Laboratories, Christchurch, New Zealand; Novartis, Horsham Research Centre, Horsham, United Kingdom; and Developmental Signalling, Cancer Research UK, London, United Kingdom. We have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. Platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane A2 (TxA2) signaling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional Gi signaling. Immunoblot analysis of platelet membranes with specific antiserum against different G subunits indicated normal levels of Gi2,Gi3,Gz, and Gq in patient platelets. However, the Gi1level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the Gi1 or Gi2 gene sequences. Our studies implicate the minor expressed Gi subtype Gi1 as having an important role in regulating signaling pathways associated with the activation of IIb3 and subsequent platelet aggregation by weak agonists. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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