Article: article from journal or magazin.
The serine protease granzyme A does not induce platelet aggregation but inhibits responses triggered by thrombin
In Vitro Journal Article Research Support, Non-U.S. Gov't --- Old month value: May 1
Granzyme A is a serine protease stored in cytoplasmic granules of cytotoxic and helper T lymphocytes. This protease seems to elicit thrombin receptor-mediated responses in neural cells, thereby triggering neurite retraction and reversal of astrocyte stellation. Here we report that granzyme A does not cause platelet aggregation even at concentrations that are more than two orders of magnitude higher than the EC50 for granzyme A in causing morphological changes in neural cells. However, granzyme A blocks thrombin-induced platelet aggregation in a dose-dependent manner without affecting the response to either ADP or to the peptide agonist of the thrombin receptor SFLLRN that corresponds in sequence to the tethered ligand domain. The inability of granzyme A to cause aggregation and its inhibition of thrombin-induced aggregation were seen in platelets from man, rat and mouse. Granzyme A does not affect the catalytic activity of thrombin in cleaving a chromogenic substrate or the macromolecular substrate fibrinogen. However, granzyme A does seem to cleave the thrombin receptor on platelets to produce a weak Ca2+ signal and reduce the response to subsequent challenge with thrombin, but does not induce a signal in thrombin-stimulated platelets. It is proposed that granzyme A interacts with the thrombin receptor found on platelets in a manner that is insufficient to cause aggregation, but sufficient to compete with thrombin for the receptor. These results suggest that granzyme A cleaves the thrombin receptor at a rate that is insufficient to cause platelet aggregation but is sufficient to cause morphological changes in neural cells. Furthermore, these observations demonstrate that granzyme A release occurring during immune responses within blood vessels would not directly cause platelet aggregation.
Amino Acid Sequence Animals Calcium/metabolism Granzymes Humans Mice Molecular Sequence Data Peptide Fragments/genetics/pharmacology Platelet Aggregation/*drug effects/physiology Platelet Aggregation Inhibitors/*pharmacology Platelet Glycoprotein GPIb-IX Complex/metabolism Rats Receptors, Thrombin/drug effects/genetics/metabolism Serine Endopeptidases/metabolism/*pharmacology Signal Transduction/drug effects T-Lymphocyte Subsets/enzymology Thrombin/metabolism/*pharmacology
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