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The role of calpain in stimulus-response coupling: evidence that calpain
mediates agonist-induced expression of procoagulant activity in platelets
JE Fox, CC Reynolds and CD Austin
Gladstone Foundation Laboratories for Cardiovascular Disease, Department of
Pathology, University of California 94140-0608.
Although calpain (the Ca2(+)-dependent protease) is widely distributed, its
function is poorly understood. One cell in which it becomes activated as a
consequence of activation of the cell is the blood platelet. The aim of the
present study was to determine whether activation of calpain was
responsible for any of the responses of platelets to stimulation. Platelets
were incubated with calpeptin, a membrane-penetrating inhibitor of calpain,
before being exposed to an agonist. Concentrations of calpeptin that
totally inhibited the agonist- induced hydrolysis of actin-binding protein
(ABP) by calpain had no effect on many other responses associated with
platelet activation: phosphorylation of myosin light chain, phosphorylation
of P47, platelet shape change, aggregation of platelets, secretion of
granule contents, or retraction of fibrin clots. However, these
concentrations of inhibitor decreased the agonist-induced generation of
procoagulant activity (assayed as the ability of platelets to catalyze the
conversion of prothrombin to thrombin in the presence of factor Va and
factor Xa). When thrombin was the agonist, the amount of ABP that was
hydrolyzed was small; only a small component of the total agonist- induced
procoagulant activity was inhibited by calpeptin. When collagen was the
agonist, more ABP was hydrolyzed and the amount of procoagulant activity
generated was greater; calpeptin decreased the collagen- induced
procoagulant activity to levels comparable with those induced by thrombin
in the presence of the inhibitor. We suggest that there are at least two
mechanisms by which procoagulant activity is generated on activated
platelets and that the agonist-induced activation of calpain mediates one
of these mechanisms. These results show that activation of calpain is a
component of the stimulus-response pathway in platelets.
Volume 76,
Issue 12,
pp. 2510-2519,
12/15/1990
Copyright © 1990 by The American Society of Hematology
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