Rhodocytin (Aggretin) Activates Platelets Lacking α2β1 Integrin, Glycoprotein VI, and the Ligand-binding Domain of Glycoprotein Ibα*

Although α2β1integrin (glycoprotein Ia/IIa) has been established as a platelet collagen receptor, its role in collagen-induced platelet activation has been controversial. Recently, it has been demonstrated that rhodocytin (also termed aggretin), a snake venom toxin purified from the venom ofCalloselasma rhodostoma, induces platelet activation that can be blocked by monoclonal antibodies against α2β1 integrin. This finding suggested that clustering of α2β1 integrin by rhodocytin is sufficient to induce platelet activation and led to the hypothesis that collagen may activate platelets by a similar mechanism. In contrast to these findings, we provided evidence that rhodocytin does not bind to α2β1 integrin. Here we show that the Cre/loxP-mediated loss of β1 integrin on mouse platelets has no effect on rhodocytin-induced platelet activation, excluding an essential role of α2β1integrin in this process. Furthermore, proteolytic cleavage of the 45-kDa N-terminal domain of glycoprotein (GP) Ibα either on normal or on β1-null platelets had no significant effect on rhodocytin-induced platelet activation. Moreover, mouse platelets lacking both α2β1 integrin and the activating collagen receptor GPVI responded normally to rhodocytin. Finally, even after additional proteolytic removal of the 45-kDa N-terminal domain of GPIbα rhodocytin induced aggregation of these platelets. These results demonstrate that rhodocytin induces platelet activation by mechanisms that are fundamentally different from those induced by collagen.

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