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Evidence for a role of glycoprotein IIb-IIIa, distinct from its ability to
support aggregation, in platelet activation by ionophores in the presence
of extracellular divalent cations
B Lages and HJ Weiss
Department of Medicine, St Luke's-Roosevelt Hospital Center, New York, NY
10019.
Ionophore A23187-induced 14C-serotonin secretion and thromboxane B2(TxB2)
formation were found to be absent in citrated platelet-rich plasma (PRP)
from thrombasthenic subjects and in normal PRP treated with glycoprotein
(GP) IIb-IIIa complex-specific monoclonal antibodies. Both responses were
restored to normal levels when 5 mmol/L EDTA was present, indicating that
their absence was not caused by the absence of aggregation per se. In
gel-filtered platelets (GFP) incubated with various additions, the blockade
or absence of GPIIb-IIIa resulted in reduced A23187-induced secretion and
TxB2 formation in media containing 1 mmol/L Ca2+ with or without fibrinogen
and 1 mmol/L Mg2+ plus fibrinogen, but not when Ca, Mg-free buffer alone, 1
mmol/L EDTA, or fibrinogen alone were present. In contrast, no such
dependence or GPIIb- IIIa was seen in GFP stimulated with thrombin or
phorbol myristate acetate in the presence of 1 mmol/L Ca2+, 1 mmol/L EDTA,
or buffer alone. The inhibition of ionophore-induced responses seen in both
normal GFP treated with antibodies and thrombasthenic GFP was not
associated with any significant alteration of the ionophore-mediated
[Ca2+]i increase, as measured in both aequorin-loaded GFP stimulated with
A23187 and fura-2-loaded GFP stimulated with ionomycin. Incubation of
normal GFP with either the monoclonal antibodies or the ligand binding site
peptide RGDS in the presence of 1 mmol/L Ca2+ caused virtually complete
inhibition of A23187-induced aggregation, measured as the loss of single
platelets, but RGDS, in contrast to the antibodies, did not inhibit
secretion or TxB2 formation. We conclude that platelet activation induced
by ionophores in the presence, but not in the absence, of extracellular
divalent cations involves a GPIIb-IIIa- dependent process that most likely
involves a property of the ligand- occupied form of the complex distinct
from its ability to support aggregation. This could represent another
example of an aggregation- independent activity of the receptor-occupied
state of the GPIIb-IIIa complex in signal transduction.
Volume 83,
Issue 9,
pp. 2549-2559,
05/01/1994
Copyright © 1994 by The American Society of Hematology
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