Glycoprotein VI-mediated platelet fibrinogen receptor activation occurs through calcium-sensitive and PKC-sensitive pathways without a requirement for secreted ADP.
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 A(2). Furthermore, protein kinase C- and calcium-regulated pathways independently contribute to GPVI-mediated platelet aggregation.
Quinton
Todd M
TM
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Ozdener
Fatih
F
Dangelmaier
Carol
C
Daniel
James L
JL
Kunapuli
Satya P
SP
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003435:Crotalid Venoms / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type; D010455:Peptides; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*; D013928:Thromboxane A2 / Q000494:pharmacology
D002352:Carrier Proteins; D003435:Crotalid Venoms; D037181:Lectins, C-Type; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; C028890:convulxin; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D002118:Calcium