Thrombin Receptor Agonist Peptide (TRAP)

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Thrombin has been shown to have a variety of cellular effects mediated by proteolytic activation of specific cell surface receptors called thrombin receptors (or “tethered ligand” receptors). Thrombin receptor, which consists of seven transmembrane domains, is a member of the G protein coupled receptor superfamily. The activation of the receptor occurs by the cleavage of an extracellular N-terminal domain by thrombin, thus exposing a new NH₂ terminal, which acts as an “anchoring ligand” and binds to an appropriate position in the receptor structure. As a result of this structural rearrangement, the receptor is activated, resulting in a variety of observable G-protein coupling signal transduction pathways. Proteolytic activated thrombin receptors have been cloned and proved to exist in many different cell types, including human platelets, endothelial cells, fibroblasts, vascular smooth muscle and cardiomyocytes. When such cells are treated with thrombin, many different reactions can be observed, many of which can be simulated by synthetic peptides corresponding to the N-terminal anchoring ligand sequence. The identification of thrombin receptors in related cell types and many of the pathophysiological effects of thrombin on these cells seem to be at least partially mediated by thrombin receptors. This suggests that thrombin receptors play a role in the pathological processes of thrombosis, inflammation, atherosclerosis and fibrous hyperplasia.

Mechanism of action

Thrombin receptor agonist peptide (TRAP-6,TRAP-14) containing 6 and 14 amino acids can induce the aggregation of washed platelets and platelets in citric acid and hirudin plasma. Platelet stimulation is related to the increase of cytoplasmic Ca²⁺ and the formation of thromboxane. In porcine pulmonary arteries, they induce reversible endothelium-dependent relaxation of precontracted vessels by releasing endothelial-derived nitric oxide. There was no significant difference in intrinsic activity between TRAP-6 and TRAP-14. Both peptides have thrombin-like activity, but their titer is more than three orders of magnitude lower than that of thrombin.

Application

Platelet activation by thrombin is critical for hemostasis and thrombosis. The TRAP is a thrombin receptor fragment, which can completely replicate the effect of thrombin on matrix metalloprotease (MMPs) in vascular endothelial cells. Studies have shown that this peptide may be a signal of a variety of thrombin responses, and has been shown to cause platelet aggregation, resulting in a wide range of G-protein dependent responses.

References

1. Bernatowicz, M. S., Klimas, C. E., Hartl, K. S., Peluso, M., Allegretto, N. J., & Seiler, S. M. (1996). Development of potent thrombin receptor antagonist peptides. Journal of medicinal chemistry, 39(25), 4879-4887.
2. Nehaj, F., Sokol, J., Mokan, M., Ivankova, J., & Mokan, M. (2018). Thrombin Receptor Agonist Peptide–Induced Platelet Aggregation Is Reduced in Patients Receiving Dabigatran. Clinical and Applied Thrombosis/Hemostasis, 24(2), 268-272.