Proteinase-activated receptors: Tethered ligands and receptor-activating peptides

Proteinase-activated receptors (PARs), newly-discovered members of the G-protein-coupled receptor superfamily, comprising four cloned family members (PARs 1 to 4), are activated by the proteolytic unmasking of a "tethered ligand" sequence situated in the N-terminal extracellular receptor domain. Furthermore, synthetic peptides with sequences based on the revealed tethered ligands can, in the absence of proteolysis, trigger receptor signaling. This report reviews the data supporting the tethered ligand mechanism of receptor activation, outlines the utility of the receptor-activating peptides (so-called PAR-APs) for exploring the potential physiological roles of the PARs, and discusses the potential differences between the activation of the receptors via their tethered ligands as opposed to activation by the soluble peptides having the same amino acid sequences. (C) 2003 Wiley-Liss, Inc.