Schematic diagram of a PAR with domains thought to play a role in receptor signaling shown by checkering. The diagram is an amalgamation of the data obtained to date with PAR₁ and PAR₂. There is limited information on PAR₃ and PAR₄. For all of the PARs, with the exception of PAR₃, the tethered ligand (TL) is central to receptor activation following proteinase unmasking. Each tethered ligand exhibits specificity for its cognate receptor, except for PAR₁, where its TL peptide sequence also shows agonist activity toward PAR₂. For PAR₁ and PAR₂, extracellular loop 2 (ECL2) has been shown to confer PAR-AP specificity for the receptor, although the role of ECL2 for activation by the proteinase-revealed tethered ligand remains to be confirmed. For PAR₂, there is believed to be an important interaction between the N terminus (NT) and extracellular loop 3 (ECL3) in that substitution of the PAR₂ domains with comparable sequences for PAR₁ results in a loss of receptor function (Lerner et al., 1996). For PAR₁, a short region of the NT (residues 83–93), in addition to an acidic residue on extracellular loop 3, have been demonstrated to play a role in PAR-AP activation (Bahou et al., 1994; Blackhart et al., 2000). Intracellular loop 2 (ICL2) has been proposed to play a role in G-protein coupling for PAR₁ (Verrall et al., 1997), whereas the cytoplasmic tail contains phosphorylation sites that are involved in signal termination and internalization of the receptor (Trejo and Coughlin, 1999; DeFea et al., 2000). PARs possess potential N-linked glycosylation sequons (61) on their NT and ECL2. Not all potential sites of glycosylation are shown. In PAR₂, NT glycosylation has been demonstrated to regulate the ability of mast cell tryptase to activate the receptor (Compton et al., 2001).