Fig. 1

PAR heterodimerization. A PAR1/PAR4—P2Y12. PAR1-PAR4 heterodimer is required for thrombin response within a wide concentration range. Activation of the G_αq pathway (black arrows), promotes ADP secretion and the consequent activation of the P2Y12 receptor. PAR4-P2Y12 dimer complex recruits β-arrestin and Akt (blue arrows) leading to the activation of integrin and platelet aggregation. On the other hand, TXA2 generation (red arrows) depends on Erk1/2 signaling triggered by the three receptors. TXA2 is involved in platelet recruitment to the site of injury. B PAR1-PAR2. PAR1 thrombin-induced activation of PAR1 in the early phases of sepsis is vascular disruptive, involving Ca²⁺ mobilization, and Rho/ROCK activity. The inclusion of PAR2 induces a switch to Rac1 signaling and the activation of β-arrestin-dependent ERK1/2 signaling, which is vascular protective. PAR1-PAR2 barrier protection can also depend on FXa. C PAR1-PAR3. Thrombin activation of PAR1-PAR3 increases barrier permeability, by stimulating G_α13 over G_αq activity. On this line, the activation of EPCR or PAR3 APC can mediate endothelial barrier protection by directly interacting activating PAR1