In this issue of the JCI, Ferrell and colleagues report that mice lacking the proteinase-activated receptor-2 (PAR-2) were protected against a form of adjuvant-induced arthritis (1). Herein we discuss protease-activated receptors, their mechanism of activation, and the contexts in which they are thought to function. A useful unifying hypothesis emerges: protease-activated receptors link tissue injury to appropriate cellular responses, and such responses, while normally homeostatic, may contribute to disease.

Protease-activated receptor-1 (PAR-1), the prototypical PAR, was identified in a search for the receptors that mediate the activation of platelets and other cells by the coagulation protease thrombin. Known to be a seven transmembrane domain G-protein–coupled receptor, PAR-1 is activated by proteolysis (Figure 1). Thrombin binds to PAR-1’s N-terminal exodomain and cleaves it after Arg41 to generate a new receptor N-terminus. The first six amino acids of this new N-terminus, SFLLRN, then serve as a tethered ligand that binds intramolecularly to the receptor’s heptahelical bundle to effect transmembrane signaling and G protein activation. Thus PARs are, in essence, peptide receptors that carry their own ligands, which lie hidden until revealed by receptor cleavage. The synthetic peptide SFLLRN, which