How the protease thrombin talks to cells

How does a protease act like a hormone to regulate cellular functions? The coagulation protease thrombin (EC 3.4.21.5) activates platelets and regulat es the behavior of other cells by means of G protein-coupled protease-activ ated receptors (PARs), PAR1 is activated when thrombin binds to and cleaves its amino terminal exodomain to unmask a new receptor amino terminus. This new amino terminus then serves as a tethered peptide ligand, binding intra molecularly to the body of the receptor to effect transmembrane signaling, The irreversibility of PAR1's proteolytic activation mechanism stands in co ntrast to the reversible ligand binding that activates classical G protein- coupled receptors and compels special mechanisms for desensitization and re sensitization, In endothelial cells and fibroblasts, activated PAR1 rapidly internalizes and then sorts to lysosomes rather than recycling to the plas ma membrane as do classical G protein-coupled receptors, This trafficking b ehavior is critical for termination of thrombin signaling. An intracellular pool of thrombin receptors refreshes the cell surface with naive receptors , thereby maintaining thrombin responsiveness. Thus cells have evolved a tr afficking solution to the signaling problem presented by PARs, Four PARs ha ve now been identified. PAR1, PAR3, and PAR4 can all be activated by thromb in, PAR2 is activated by trypsin and by trypsin-like proteases but not by t hrombin, Recent studies with knockout mice, receptor-activating peptides, a nd blocking antibodies are beginning to define the role of these receptors in vivo.