Distinct glycoprotein Ib/V/IX and integrin αIIbβ3-dependent calcium signals cooperatively regulate platelet adhesion under flow

Warwick S. Nesbitt, Suhasini Kulkarni, Simon Giuliano, Isaac Goncalves, Sacha M. Dopheide, Cindy L. Yap, Ian S. Harper, Hatem H. Salem, Shaun P. Jackson

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Abstract

We have investigated the calcium signaling relationship between the two major platelet adhesion receptors, glycoprotein Ib/V/IX (GPIbN/IX) and integrin αIibβ3, involved in regulating platelet adhesion on von Willebrand factor (vWf) under flow. Our studies demonstrate that GPIb engagement of immobilized vWf elicits a transient calcium spike that may function to promote reversible arrest of translocating platelets. Subsequent integrin αIIbβ3 engagement of vWf promotes sustained calcium oscillations that are essential for the maintenance of irreversible adhesion. GPIb-induced calcium spikes appear distinct from those initiated by integrin αIIbβ3, in that the former are exclusively mediated through release of intracellular calcium stores via a signaling mechanism independent of PI 3-kinase. In contrast, integrin αIIbβ3-dependent calcium flux involves a PI 3-kinase-dependent signaling mechanism linked to intracellular calcium mobilization and subsequent transmembrane calcium influx. Studies employing the caged calcium chelator (o-nitrophenyl-EGTA) demonstrate that transient calcium spikes initiate a transient phase of platelet arrest that is converted to irreversible adhesion with the development of sustained oscillatory calcium flux. These studies demonstrate the existence of a dual step calcium signaling mechanism utilized by GPIb and integrin αIIbβ3 that serves to regulate the dynamics of platelet adhesion under flow.

Original languageEnglish
Pages (from-to)2965-2972
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number4
DOIs
Publication statusPublished - 25 Jan 2002

Cite this

Nesbitt, Warwick S. ; Kulkarni, Suhasini ; Giuliano, Simon ; Goncalves, Isaac ; Dopheide, Sacha M. ; Yap, Cindy L. ; Harper, Ian S. ; Salem, Hatem H. ; Jackson, Shaun P. / Distinct glycoprotein Ib/V/IX and integrin αIIbβ3-dependent calcium signals cooperatively regulate platelet adhesion under flow. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 4. pp. 2965-2972.
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abstract = "We have investigated the calcium signaling relationship between the two major platelet adhesion receptors, glycoprotein Ib/V/IX (GPIbN/IX) and integrin αIibβ3, involved in regulating platelet adhesion on von Willebrand factor (vWf) under flow. Our studies demonstrate that GPIb engagement of immobilized vWf elicits a transient calcium spike that may function to promote reversible arrest of translocating platelets. Subsequent integrin αIIbβ3 engagement of vWf promotes sustained calcium oscillations that are essential for the maintenance of irreversible adhesion. GPIb-induced calcium spikes appear distinct from those initiated by integrin αIIbβ3, in that the former are exclusively mediated through release of intracellular calcium stores via a signaling mechanism independent of PI 3-kinase. In contrast, integrin αIIbβ3-dependent calcium flux involves a PI 3-kinase-dependent signaling mechanism linked to intracellular calcium mobilization and subsequent transmembrane calcium influx. Studies employing the caged calcium chelator (o-nitrophenyl-EGTA) demonstrate that transient calcium spikes initiate a transient phase of platelet arrest that is converted to irreversible adhesion with the development of sustained oscillatory calcium flux. These studies demonstrate the existence of a dual step calcium signaling mechanism utilized by GPIb and integrin αIIbβ3 that serves to regulate the dynamics of platelet adhesion under flow.",
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Distinct glycoprotein Ib/V/IX and integrin αIIbβ3-dependent calcium signals cooperatively regulate platelet adhesion under flow. / Nesbitt, Warwick S.; Kulkarni, Suhasini; Giuliano, Simon; Goncalves, Isaac; Dopheide, Sacha M.; Yap, Cindy L.; Harper, Ian S.; Salem, Hatem H.; Jackson, Shaun P.

In: Journal of Biological Chemistry, Vol. 277, No. 4, 25.01.2002, p. 2965-2972.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Nesbitt, Warwick S.

AU - Kulkarni, Suhasini

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AU - Goncalves, Isaac

AU - Dopheide, Sacha M.

AU - Yap, Cindy L.

AU - Harper, Ian S.

AU - Salem, Hatem H.

AU - Jackson, Shaun P.

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