Of all the body systems, the gastrointestinal tract is the most exposed to proteinases. Under physiological conditions, digestive proteinases such as trypsin are released in pancreatic ducts and then into the upper gastrointestinal tract, during and after meals. The forms of proteinases released in the pancreatic duct and intestinal lumen are inactive and need to be cleaved to be activated. This cleavage occurs in the gut lumen where a constant balance between proteolytic activity and the presence of proteinase inhibitors persists in order to fulfil the digestive functions of the gastrointestinal tract, but also at the same time to protect mucosal surfaces from exposure to proteolytic enzymes. The intestinal lumen is also constantly exposed to proteases potentially released from the commensal flora, but also in pathophysiological conditions to proteinases released by infectious agents. Thus the importance of signalling pathways activated by proteinases appears to be particularly relevant for the physiology and pathophysiology of the gastrointestinal tract.

PARS: ACTIVATION AND DISTRIBUTION IN THE GUT

Proteinase activated receptors (PARs) are seven transmembrane domain receptors that are activated by specific proteolytic cleavage of their N terminal extracellular domain. This cleavage releases a new motif of amino acids on the N terminal tail which then binds the receptor like an agonist to induce an intracellular signal (see fig 1). The discovery of this family of receptors highlighted a new way of thinking about the role of proteinases, that cannot be seen merely as degradative enzymes, but that can directly and specifically send signals to cells.

Four members of the PAR family have been described: PAR₁, PAR₂, PAR₃, …