The cleaved peptide of the thrombin receptor is a strong platelet agonist
Center for Platelet Function Studies; Department of Pediatrics
Amino Acid Sequence; Androstadienes; Blood Platelets; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Genistein; Humans; Molecular Sequence Data; Peptide Fragments; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Glycoprotein GPIb-IX Complex; Signal Transduction; Staurosporine
Life Sciences | Medicine and Health Sciences
Thrombin cleaves its G-protein-linked seven-transmembrane domain receptor, thereby releasing a 41-aa peptide and generating a new amino terminus that acts as a tethered ligand for the receptor. Peptides corresponding to the new amino terminal end of the proteolyzed seven-transmembrane domain thrombin receptor [TR42-55, SFLLRNPNDKYEPF, also known as TRAP (thrombin receptor-activating peptide)], previously have been demonstrated to activate the receptor. In this study, we demonstrate that the 41-aa cleaved peptide, TR1-41 (MGPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPR) is a strong platelet agonist. TR1-41 induces platelet aggregation. In whole-blood flow cytometric studies, TR1-41 was shown to be more potent than TR42-55 and almost as potent as thrombin, as determined by the degree of increase in: (i) platelet surface expression of P-selectin (reflecting alpha granule secretion); (ii) exposure of the fibrinogen binding site on the glycoprotein (GP) IIb-IIIa complex; and (iii) fibrinogen binding to the activated GPIIb-IIIa complex. As determined by experiments with inhibitors [prostaglandin I2, staurosporine, wortmannin, the endothelium-derived relaxing factor congener S-nitroso-N-acetylcysteine (SNAC), EDTA, EGTA, and genestein], and with Bernard-Soulier or Glanzmann's platelets, we demonstrated that TR1-41-induced platelet activation is: (i) inhibited by cyclic AMP; (ii) mediated by protein kinase C, phosphatidyl inositol-3-kinase, myosin light chain kinase, and intracellular protein tyrosine kinases; (iii) dependent on extracellular calcium; and (iv) independent of the GPIb-IX and GPIIb-IIIa complexes. TR1-41-induced platelet activation was synergistic with TR42-55. In summary, the cleaved peptide of the seven-transmembrane domain TR (TR1-41) is a strong platelet agonist.
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3082-7.
Proceedings of the National Academy of Sciences of the United States of America
Furman MI, Liu L, Benoit SE, Becker RC, Barnard MR, Michelson AD. (1998). The cleaved peptide of the thrombin receptor is a strong platelet agonist. Open Access Publications by UMMS Authors. Retrieved from https://escholarship.umassmed.edu/oapubs/1792