Protease-activated receptors: how proteases signal to cells

Certain proteases from the circulation, mast cells and elsewhere signal directly to cells by cleaving protease-activated receptors (PARs), members of a new subfamily of G-protein-coupled receptor. Cleavage exposes a tethered ligand domain that binds to and activates the cleaved receptors. Advances in the past year have improved our understanding of the molecular mechanisms of this signaling and how it is switched off. It is now recognized that PARs play important roles in ‘emergency situations’ — such as trauma, when there is generation or release of proteases — and are involved in coagulation, inflammation, pain, healing and protection. Selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases. The intriguing mechanisms that allow proteases to cleave and activate a family of G-protein-coupled receptors are becoming clear, as are the roles of these receptors in disease, especially in the gastrointestinal tract.