Evidence for cross-talk between glycoprotein VI and Gi-coupled receptors during collagen-induced platelet aggregation.
Collagen-induced platelet aggregation is a complex process and involves synergistic action of integrins, immunoglobulin (Ig)-like receptors, G-protein-coupled receptors and their ligands, most importantly collagen itself, thromboxane A(2) (TXA(2)), and adenosine diphosphate (ADP). The precise role of each of these receptor systems in the overall processes of activation and aggregation, however, is still poorly defined. Among the collagen receptors expressed on platelets, glycoprotein (GP) VI has been identified to play a crucial role in collagen-induced activation. GPVI is associated with the FcRgamma chain, which serves as the signal transducing unit of the receptor complex. It is well known that clustering of GPVI by highly specific agonists results in platelet activation and irreversible aggregation, but it is unclear whether collagen has the same effect on the receptor. This study shows that platelets from Galphaq-deficient mice, despite their severely impaired response to collagen, normally aggregate on clustering of GPVI, suggesting this not to be the principal mechanism by which collagen activates platelets. On the other hand, dimerization of GPVI by a monoclonal antibody (JAQ1), which by itself did not induce aggregation, provided a sufficient stimulus to potentiate platelet responses to Gi-coupled, but not Gq-coupled, agonists. The combination of JAQ1 and adrenaline or ADP, but not serotonin, resulted in alpha(IIb)beta(3)-dependent aggregation that occurred without intracellular calcium mobilization and shape change in the absence of Galphaq or the P2Y(1) receptor. Together, these results provide evidence for a cross-talk between (dimerized) GPVI and Gi-coupled receptors during collagen-induced platelet aggregation. (Blood. 2001;97:3829-3835)
Nieswandt
B
B
Department of Molecular Oncology, General Surgery, Witten/Herdecke University, Arrenbergerstrasse 20, 42117 Wuppertal, Germany. nieswand@klinikum-wuppertal.de
Bergmeier
W
W
Eckly
A
A
Schulte
V
V
Ohlmann
P
P
Cazenave
J P
JP
Zirngibl
H
H
Offermanns
S
S
Gachet
C
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D004357:Drug Synergism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D008565:Membrane Proteins; C548577:P2ry12 protein, mouse; D010980:Platelet Membrane Glycoproteins; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; C098341:platelet membrane glycoprotein VI; D003094:Collagen; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins