A PLC gamma 2-independent platelet collagen aggregation requiring functional association of GPVI and integrin alpha2beta1.
The role of the phospholipase C (PLC)gamma 2 isotype in platelet activation was evaluated by studying PLC gamma 2 -/- mice. These mice have a prolonged bleeding time but their platelets respond normally to non-collagenous agonists. PLC gamma 2-null platelets show residual aggregation response to collagen fibres (6% versus 74% for wild-type) with minimal granule secretion and no shape change. A delayed shape change is observed at later aggregation times. Specific activation by glycoprotein (GP)VI agonists (convulxin, collagen-related peptide and GPVI crosslinking) is, however, abolished. Antibodies against integrin alpha(2)beta(1) and GPVI each inhibit the residual collagen response, implying a role of alpha(2)beta(1) in platelet activation and a functional association with GPVI. These responses are also prevented by blocking integrin alpha(IIb)beta(3) and phosphoinositide 3-kinase, whereas aspirin treatment and ADP receptor blockade only inhibit shape change. These results provide evidence for a PLC gamma 2-independent collagen activation pathway requiring cooperation between GPVI and alpha(2)beta(1) leading to alpha(IIb)beta(3)-dependent aggregation and shape change by released ADP and thromboxane A(2).
Mangin
P
P
INSERM U.311, Etablissement Français du Sang-Alsace, 10 rue Spielmann, BP 36, 67065 Strasbourg Cedex, France.
Nonne
C
C
Eckly
A
A
Ohlmann
P
P
Freund
M
M
Nieswandt
B
B
Cazenave
J P
JP
Gachet
C
C
Lanza
F
F
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D003094:Collagen / Q000494:pharmacology*; D038982:Integrin alpha2beta1 / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D022142:Secretory Vesicles / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000502:physiology*
D038982:Integrin alpha2beta1; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma