TRAP-6 is a selective protease-activated receptor 1 (PAR1) agonist composed of six amino acids. TRAP-6 has a relatively simple and compact overall structure, existing as a flexible linear peptide. This structural flexibility facilitates conformational changes upon receptor binding, thereby triggering downstream signaling[1]. TRAP-6 is commonly used in research on platelet function, coagulation mechanisms, and cardiovascular diseases[2,3].
In vitro, treatment of wild-type mouse microglial cells with TRAP-6 (100, 200μM) for 24h significantly induced cell proliferation[4]. In decidual stromal cells (DSCs), TRAP-6 (100μM) treatment for 8h significantly upregulated the mRNA expression of IL-8, MCP-1, and MMP-1[5]. Pre-treatment of human washed platelets with the P2Y12 inhibitor MRS2395 (10μM) for 15min, followed by stimulation with TRAP-6 (10μM) for 30s, significantly enhanced TRAP-6-induced dense granule release, increased cytosolic Ca2+ levels, and promoted phosphorylation of GSK3β-Ser9[6].
In vivo, intraperitoneal injection of TRAP-6 (10mg/kg; three times/week) for 3 weeks in a C57BL/6→BALB/c acute graft-versus-host disease (GvHD) mouse model significantly reduced GvHD clinical scores, improved survival rates, and ameliorated histopathological damage in the colon and liver[7]. Topical application of TRAP-6 (2mM; 30μL) to skin wounds in Nembutal-anesthetized rats significantly activated mast cells in the subcutaneous adipose tissue after 3 days, resulting in a 5.4-fold decrease in heparin content within mast cells and a marked increase in degranulation and granulolysis indices[8].
References:
[1] ANDERLUH M, DOLENC M. Thrombin receptor antagonists, recent advances in PAR-1 antagonist development[J]. Current Medicinal Chemistry, 2002, 9(13): 1229-1250.
[2] WEBER M, GERDSEN F, GUTENSOHN K, et al. Enhanced platelet aggregation with TRAP-6 and collagen in platelet aggregometry in patients with venous thromboembolism[J]. Thrombosis Research, 2002, 107(6): 325-328.
[3] MÉNDEZ D, URRA F A, MILLAS-VARGAS J P, et al. Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6[J]. European Journal of Medicinal Chemistry, 2020, 192: 112187.
[4] SUO Z, WU M, AMEENUDDIN S, et al. Participation of protease-activated receptor-1 in thrombin-induced microglial activation[J]. Journal of Neurochemistry, 2002, 80(4): 655-666.
[5] GOTO K, KAWANO Y, UTSUNAMIYA T, et al. Decidualization modulates a signal transduction system via protease-activated receptor-1 in endometrial stromal cells[J]. American Journal of Reproductive Immunology, 2018, 80(5): e13036.
[6] MITRUGNO A, RIGG R A, LASCHOBER N B, et al. Potentiation of TRAP-6-induced platelet dense granule release by blockade of P2Y12T activating GPR15[J]. Leukemia, 2024, 38(6): 1390-1402.
[8] UMAROVA B A, DUGINA T N, SHESTAKOVA E V, et al. Activation of rat mast cells upon stimulation of protease-activated receptor (PAR-1)[J]. Bulletin of Experimental Biology and Medicine, 2000, 129(4): 314-317.