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Bacitracin reveals a role for multiple thiol isomerases in platelet function
Author(s) -
Robinson Aisling,
O'Neill Sarah,
Kiernan Aoife,
O'Donoghue Niaobh,
Moran Niamh
Publication year - 2006
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05878.x
Subject(s) - thiol , isomerase , biochemistry , platelet , protein disulfide isomerase , bacitracin , chemistry , integrin , platelet activation , enzyme , biology , receptor , immunology , antibiotics
Summary The platelet‐specific integrin α IIb β 3 has endogenous thiol isomerase activity associated with the CXXC motifs within the β subunit. Using a highly purified form of bacitracin, a thiol isomerase inhibitor, we now provide further evidence of the functional significance of this enzymatic activity in integrin activation. In addition, we demonstrate a role for multiple thiol isomerases in platelet function. This bacitracin prevented platelet aggregation to thrombin and collagen, and directly inhibited α IIb β 3 activation, as detected by PAC‐1 binding. In parallel, bacitracin inhibited the endogenous thiol isomerase activity of purified α IIb β 3 with a 50% inhibitory concentration of 15·5 μ mol/l. In order to determine whether the effects of bacitracin are solely mediated by inhibition of integrin enzymatic activity, we examined integrin‐independent indices of platelet activation. We found bacitracin inhibited both platelet secretion (CD62P and CD63) and thromboxane (TxA 2 ) production, with complete inhibition at different concentrations. Thus, we demonstrated a role for multiple thiol isomerases in platelet function. Taken together, these studies support a role for the endogenous integrin thiol isomerase activity in activation of α IIb β 3 and highlight the novel regulation of platelet function by other, as yet undefined thiol isomerases.