Protease activated receptor 2: a new target for IBS treatment.

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that are activated by the proteolytic cleavage of their N-terminal domain. The new N-terminal sequence that is exposed by proteolysis acts as a tethered ligand, which binds to and activates the receptor. PAR-2 is highly expressed in the gastrointestinal tract, where it is found in endothelial cells, colonic myocytes, enterocytes (both on basolateral and apical membranes), enteric neurons, terminals of mesenteric afferent nerves and immune cells. In the gastrointestinal tract, PAR-2 may be activated by tryptase from mast cells but also by luminal proteases such as trypsin and possibly bacterial proteases. In addition to effects on motility, ion and mucus secretion, activation of PAR-2 receptors from luminal affects visceral pain. In rats, the intracolonic infusion of PAR-2 agonists (SLIGRL, trypsin) initiates a delayed hypersensitivity to colonic distension. These effects are locally mediated since they are not observed for systemic administration. Interestingly, such pronociceptive effect of local activation of PAR-2 is associated with increased colonic paracellular permeability. Blockade of such increase in permeability, prevents the occurrence of hypersensitivity to rectal distension suggesting that activation of the local immune system by luminal toxins and antigens is responsible for the sensitization of primary afferent terminals to mechanical stimuli. Consequently, blockade of PAR-2 receptors at the periphery and/or inhibition of colonic luminal protease activity may be new interesting targets for the treatment of gut hypersensitivity and IBS. A recent study has evidenced that stool supernatants from diarrhea predominant IBS patients have a high level of serine-protease activity that increases permeability and colonic hypersensitivity when infused intra-colonically in mice, and these effects are linked to activation of PAR-2 receptors. These data support a possible role of luminal proteases in the pathogenesis of IBS and give a rationale to target PARs and more specifically PAR-2 as future treatment of IBS.