Secretion Aggregation

FIGURE 3: Hie two receptor model of thrombin-induced platelet activation. See text for details. Modified from '8, with permission.

3 protein) can be co-immunoprecipitated with GPIb69 but the role of this interaction in the effects of a-thrombin on platelets, as compared with those of vWF, remains to be elucidated. However, the TLP-independent events described earlier, such as the sustained activation of p42/44m*pk and other kinases and their translocation to the cytoskeleton may be provisionally assigned to this high affinity GPIb-dependent pathway. The Ca2+ pool mobilized by this receptor may be different from that mobilized by the moderate affinity, PARI-dependent pathway since immunoinhibition reaches a maximum of 50% in each case.

Taking the two receptor model as a whole, it may be noted that those activities which have been shown to require continuous receptor occupancy, such as arachidonate mobilization and the formation of phosphatide acid, are mediated through the high affinity pathway and represent a receptor-ligand mediated mechanism while those receptor activities that require only transient receptor occupancy, such as the synthesis and breakdown of phosphoinositides, correspond to the moderate affinity proteolytic PARI pathway. The feet that immunoinhibitoiy effects at either receptor can be overcome at elevated thrombin levels merely indicates the relatively high affinities of thrombin binding at both sites (~0.5nM and lOnM, respectively) as compared with the relatively low affinities of the binding antibodies; for example the Kd of the binding of ATAP138 to PARI is ~80nM.29

In summary, the available evidence strongly supports the two receptor model for thrombin-induced platelet activation. In this model a supercomplexed form of GPIb acts as the high affinity receptor while PARI acts as the moderate affinity receptor. The applicability of this model in other cell systems, and the relative contributions of the two receptor pathways in the normal or pathophysiological activation of platelets, remain to be determined.


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