Activation of GPVI by collagen is regulated by alpha2beta1 and secondary mediators.
We have compared the roles of adenosine diphosphate (ADP), thromboxanes and the integrin alpha(2)beta(1) in the activation of washed platelets by collagen in the presence of the alpha(IIb)beta(3) antagonist lotrafiban. The stimulation of protein tyrosine phosphorylation by a collagen suspension is markedly delayed in the presence of the above inhibitors but shows substantial recovery with time. In comparison, activation of phospholipase C (PLC), Ca(2+) elevation and dense granule secretion are more severely suppressed by the above inhibitors. alpha(2)beta(1) blockade has a slightly greater inhibitory effect on all of the above responses than a combination of ADP receptor antagonists and cyclooxygenase inhibitor. Platelets exposed to a collagen monolayer show robust elevation of Ca(2+) that is delayed in the presence of the above inhibitors and which is accompanied by alpha-granule secretion. These results demonstrate that secondary mediators and alpha(2)beta(1) modulate collagen-induced intracellular signaling but have negligible effect on GPVI signaling induced by the specific agonist convulxin. This work supports the postulate that the major role of alpha(2)beta(1) is to increase the avidity of collagen for the platelet surface and by doing so enhance activation of GPVI. Therefore we propose an important role of secondary mediators in collagen-induced signaling is the indirect regulation of GPVI signaling via activation of alpha(2)beta(1).
Atkinson
B T
BT
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. ben.atkinson@pharm.ox.ac.uk
Jarvis
G E
GE
Watson
S P
SP
D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling; D003094:Collagen / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D038982:Integrin alpha2beta1 / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D017482:Receptors, Thromboxane / Q000502:physiology
D038982:Integrin alpha2beta1; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010980:Platelet Membrane Glycoproteins; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D017482:Receptors, Thromboxane; C098341:platelet membrane glycoprotein VI; D003094:Collagen; D043802:GTP-Binding Protein alpha Subunits, Gq-G11