Activation mechanism of protease activated receptor (PAR). PARs are a group of four G protein-coupled receptors (GPCRs). Activation of PARs depends on the protease cleavage at the specific site of the extracellular N-terminal, upon which the exposed tethered ligand (gray square) binds to the second extracellular loop of PAR resulting in a series of cellular signaling events. The red arrow indicates cleavage site. The site for PAR-1 is at LDPR41↓S42FLLRN, PAR-2 is at SKGR34↓S35SLIGKV, PAR-3 is at LPIK38↓T39FRGAP, and PAR-4 is at PAPR47↓G48 YPGQV. PAR-2 antagonist peptide: FSLLRY-NH2; SCH 79797: a PAR-1 antagonist; the active peptides were PAR-1: SFLLR-NH2, TFLLRN-NH2; PAR-2: SLIGKV-NH2, transcinnamoyl- (tc-) LIGRLO-NH2; and PAR-3: TFRGAP-NH2 PAR-4, GYPGQV-NH2. S = Ser, F = Phe, L = Leu, R = Arg, T = Thr, I = Ile, G = Gly, K = Lys, V = Val, O = Pyl, A = Ala, P = Pro, Y = Tyr, Q = Gln, and V = Val.