SHEDDING OF ADHESION RECEPTORS FROM THE SURFACE OF ACTIVATED PLATELETS

When platelets are activated, several receptors are removed from the p latelet surface. Cytoskeletal reorganizations can cause receptors to r edistribute to intracellular membranes. In addition, receptors can be removed from the platelet surface by shedding of the receptor from the cell. Shedding can occur by at least two mechanisms. First, glycoprot ein (GP) Ib(alpha) and GP V are shed from the membrane as a result of the proteolytic cleavage of the extracellular domain of these receptor s from the platelet. The protease responsible for this cleavage appear s to be a membrane-bound divalent cation-dependent protease other than calpain. Proteolytic cleavage does not occur until secretion is well under way and occurs whether platelets aggregate or not. Soluble forms of both GP Ib(alpha) and GP V are present in the plasma, where they m ay serve as feedback inhibitors limiting the development of thrombi. F uture studies will be needed to identify the protease(s) responsible f or removing the membrane receptors and to determine whether cleavage o f the receptors from activated platelets results from activation of th e protease(s), exposure of the protease(s), or an altered exposure of the protease-sensitive sites on the receptors. It will be of particula r interest to determine whether the protease(s) that cleaves GP Ib(alp ha) and GP V in platelets is the same as the protease(s) that cleaves receptors from the surface of other activated cells. Receptors also ar e shed from the surface of activated platelets by the generation of mi crovesicles from the plasma membrane. These microvesicles appear to co ntain all of the major membrane glycoproteins but are depleted in thos e that have been removed from the platelet membrane by proteolytic cle avage. The primary mechanism responsible for the shedding of microvesi cles from the surface of platelets stirred with physiological agonists involves activation of calpain, which cleaves components of the membr ane skeleton and dissociates it from the plasma membrane GP Ib-IX comp lex. Microvesicles are present in the circulation and increase under c onditions in which platelet activation is known to have occurred. Beca use they contain functional adhesive receptors and procoagulant activi ty on their surface, they may function to disseminate procoagulant act ivity and stabilize the formation of platelet clots.