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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 (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 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 Patel, Y. M Articles by Savidge, G. Search for Related Content PubMed PubMed Citation Articles by Patel, Y. M Articles by Savidge, G. Social Bookmarking                   What's this? Submitted October 16, 2002 Accepted February 12, 2003 Evidence for a role for Gi1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Gi1 expression and defective Gi signalling in the platelets of a patient suffering from a chronic bleeding disorder Yatin M Patel*, Kirti V Patel, Salman Rahman, Mark P Smith, Gillian Spooner, Rushika N Sumathipala, Michael Mitchell, Geraldine Flynn, Alexandra Aitken, and Geoffrey Savidge The Coagulation Research Laboratory, Division of Medicine, GKT School of Biomedical Sciences, London, United Kingdom The Haemophilia Reference Centre, Centre for Thrombosis and Haemostasis, St Thomas Hospital, London, United Kingdom * Corresponding author; email: yatin.m.patel{at}kcl.ac.uk. We have examined platelet functional responses and characterised a novel-signalling 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) signalling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilisation of intracellular calcium, diacylglycerol (DAG) generation or pleckstrin phosphorylation. In comparison, Gi-mediated signalling induced by either thrombin, ADP or adrenaline, examined by suppression of forskolin stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional Gisignalling. Immunoblot analysis of platelet membranes with specific antiserum against different G subunits indicated normal levels of Gi2, Gi3, Gzand Gqin patient platelets. However, Gi1levels were reduced to 25% of that found in membranes prepared from normal platelets. Analysis of platelet cDNA and genomic DNA revealed no abnormality in either the Gi1 or Gi2 gene sequences. Our studies implicate the minor expressed Gisubtype, Gi1, as having an important role in regulating signalling 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? This article has been cited by other articles: D. J. Angiolillo, D. Capodanno, and S. Goto Platelet thrombin receptor antagonism and atherothrombosis Eur. Heart J., November 30, 2009; (2009) ehp504v1. [Abstract] [Full Text] [PDF]

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