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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3228-3234
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Glycoprotein VI-mediated platelet fibrinogen receptor activation
occurs through calcium-sensitive and PKC-sensitive pathways
without a requirement for secreted ADP
Todd M. Quinton,
Fatih Ozdener,
Carol Dangelmaier,
James L. Daniel, and
Satya P. Kunapuli
From the Departments of Physiology, Pharmacology, and
the Sol Sherry Thrombosis Research Center, Temple University School of
Medicine, Philadelphia, PA.
Collagen activates platelets by transducing signals through
glycoprotein VI (GPVI). It is not clear whether collagen can directly activate fibrinogen receptors on the adherent platelets without a role
for positive feedback agonists. We investigated the contribution of
secondary G protein signaling to the mechanism of GPVI-stimulated platelet aggregation using the GPVI-selective agonists, convulxin and
collagen-related peptide (CRP) as well as collagen. Adenosine diphosphate (ADP) scavengers or ADP receptor antagonists shifted the
concentration-response curve slightly to the right at low concentrations of convulxin, whereas platelet aggregation at higher concentrations of convulxin was unaffected by these agents. ADP receptor antagonists shifted the concentration-response curve of
collagen- or CRP-induced platelet aggregation to the right at all the
concentrations. Protein kinase C inhibitor, Ro 31-8220, or a
calcium chelator 5,5'-dimethyl-BAPTA shifted the
concentration-response curve of convulxin-induced platelet aggregation
to the right. In addition, pretreatment with both Ro 31-8220 and
dimethyl-BAPTA resulted in total inhibition of convulxin-mediated
aggregation. Blockade of either the calcium- or protein kinase
C-regulated pathway leads to inhibition of fibrinogen receptor
activation on platelets adherent to collagen, but inhibition of both
pathways leads to abolished fibrinogen receptor activation. We conclude that collagen-induced activation of fibrinogen receptor on adherent platelets through GPVI signaling occurs without any significant role
for secreted ADP or thromboxane A2. Furthermore, protein kinase C- and calcium-regulated pathways independently contribute to
GPVI-mediated platelet aggregation.
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