Biased agonism of PAR1 resulting from canonical cleavage at Arg41 by thrombin or by noncanonical cleavage at Arg46 by APC. PAR1 is a biased receptor with biased agonists.¹⁸  Four different PAR1 agonists are shown along the top bar that can vary in their ability and efficacy to activate different signaling pathways in cells, thus depicting a signaling phenomenon that has been labeled “functional selectivity” or “biased agonism.” The receptor's bias is directly based on the spectrum of signaling that is mediated either via 1 or more G proteins or via β-arrestin-2, whereas the agonist bias is directly related to the sites of cleavage in the extracellular N-terminus (ie, resulting from cleavage either at Arg41 or at Arg46). The TRAP peptide(s) represent the N-terminal sequence of PAR1 that exists after cleavage at Arg41, whereas TR47 represents the N-terminal sequence of PAR1 that exists after cleavage at Arg46, as described in this report. Each agonist can have distinctly different properties because each one can stabilize a different subset of the dynamic conformational ensembles of PAR1. The conformer subsets that are stabilized by TRAP and thrombin promote signaling via different G proteins, whereas conformer subsets stabilized by APC's action, and presumably TR47, promote signaling via β-arrestins, especially β-arrestin-2, and dishevelled-2. However, one must note that TRAP is similar but not functionally equivalent to thrombin; and it is probable, but not yet shown, that the TR47 peptide does not have all the same activities and efficacy as APC. Not depicted are the effects of MMP1 cleavage at Asp39 in PAR1 or potential allosteric PAR1 modulatory factors, including binding of thrombin to the hirudin-like sequence of PAR1, localization of PAR1 in caveolae with caveolin-1, association with EPCR containing bound protein C or APC, dimerization with other PARs, or small molecular allosteric modulators.^41,46