PARticipation in inflammation

Abstract

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 ​(Figure1).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 mimics the PAR-1 tethered ligand, is a PAR-1 agonist and activates PAR-1 independent of thrombin and receptor cleavage. Such peptide agonists have provided a ready tool for probing the effects of PAR activation in vitro and in vivo. Figure 1 Mechanism of PAR-1 activation. The N-terminus of PAR-1, a seven transmembrane domain G protein–coupled receptor, contains a protease cleavage site that, once cleaved by thrombin, results in a new N-terminus. The new N-terminal sequence, SFLLRN, ... Four PARs are currently known (recent reviews include refs. 2–4). PAR-1, PAR-3, and PAR-4 can be activated by thrombin, and thrombin is almost certainly a physiological activator of these receptors in vivo. Several other proteases can cleave these receptors productively and may also contribute to their function in vivo. PAR-2 can be activated by multiple trypsin-like serine proteases including: trypsin itself, mast cell tryptase, neutrophil proteinase 3, tissue factor/factor VIIa/factor Xa, and membrane-tethered serine protease-1. However PAR-2 is not cleaved by thrombin.