Transmembrane calcium influx associated with von Willebrand factor binding to GP Ib in the initiation of shear-induced platelet aggregation.
We found that the binding of multimeric vWF to GP Ib under a shear force of 108 dynes/cm2 resulted in the transmembrane flux of Ca2+ ions with a two- to three-fold increase in their intracellular concentration ([Ca2+]i). The blockage of this event, obtained by inhibiting the vWF-GP Ib interaction, suppressed aggregation. In contrast, the blockage of vWF binding to GP IIb-IIIa, as well as the prevention of activation caused by increased intracellular cAMP levels, inhibited aggregation but had no significant effect on [Ca2+]i increase. A monomeric recombinant fragment of vWF containing the GP Ib-binding domain of the molecule (residues 445-733) prevented all effects mediated by multimeric vWF but, by itself, failed to support the increase in [Ca2+]i and aggregation. These results suggest that the binding of multimeric vWF to GP Ib initiates platelets aggregation induced by high shear stress by mediating a transmembrane flux of Ca2+ ions, perhaps through a receptor-dependent calcium channel. The increase in [Ca2+]i may act as an intracellular message and cause the activation of GP IIb-IIIa; the latter receptor then binds vWF and mediates irreversible aggregation.
Department of Hematology, Keio University School of Medicine, Tokyo, Japan.
Y
Y
Ikeda
M
M
Handa
T
T
Kamata
K
K
Kawano
Y
Y
Kawai
K
K
Watanabe
K
K
Kawakami
K
K
Sakai
M
M
Fukuyama
I
I
Itagaki
D001692:Biological Transport; D001792:Blood Platelets / Q000378:metabolism*; D001809:Blood Viscosity; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010974:Platelet Aggregation; D010979:Platelet Function Tests / Q000295:instrumentation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013314:Stress, Mechanical; D013915:Thrombasthenia / Q000097:blood; D014841:von Willebrand Factor / Q000378:metabolism*
D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; C028254:von Willebrand factor receptor; D002118:Calcium