Differential roles of integrins α₂β₁ and α_IIbβ₃ in collagen and CRP-induced platelet activation

Abstract

Collagen and collagen-related peptide (CRP) activate platelets by interacting with glycoprotein (GP)VI. In addition, collagen binds to integrin α₂β₁ and possibly to other receptors. In this study, we have compared the role of integrins α₂β₁ and α_IIbβ₃ in platelet activation induced by collagen and CRP. Inhibitors of ADP and thromboxane A₂ (TxA₂) substantially attenuated collagen-induced platelet aggregation and dense granule release, whereas CRP-induced responses were only partially inhibited. Under these conditions, a proportion of platelets adhered to the collagen fibres resulting in dense granule release and α_IIbβ₃ activation. This adhesion was substantially mediated by α₂β₁. The α_IIbβ₃ antagonist lotrafiban potentiated CRP-induced dense granule release, suggesting that α_IIbβ₃ outside-in signalling may attenuate GPVI signals. By contrast, lotrafiban inhibited collagen-induced dense granule release. These results emphasise the differential roles of α₂β₁ and α_IIbβ₃ in platelet activation induced by collagen and CRP. Further, they show that although ADP and TxA₂ greatly facilitate collagen-induced platelet activation, collagen can induce full activation of those platelets to which it binds in the absence of these mediators, via a mechanism that is dependent on adhesion to α₂β₁.