Activation of proteinase activated receptor‐2 (PAR‐2) inhibits spontaneous activity in rat colon

Abstract

Proteolytic cleavage of proteinase activated receptor‐2 (PAR‐2) reveals a tethered ligand which binds to and activates the receptor. Rat colonic smooth muscle shows spontaneous contractile activity which is generated by pacemaker cells. This study investigated the effects of PAR‐2 activation on spontaneous contractile activity in the isolated rat colon.Strips of rat colon longitudinal muscle were suspended in organ baths and increasing concentrations of trypsin, or the mimetic peptide FLIGRL, were applied. In some experiments carbachol was used to increase smooth muscle tone.Trypsin and FLIGRL each induced concentration‐dependent inhibition of spontaneous contractile activity of rat colon. Trypsin‐evoked relaxations (66.6±3.3; n=8) were abolished by apamin, an inhibitor of small conductance Ca2+‐activated potassium channels (SKCa). Similar results were obtained with FLIGRL (n=5). Cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca2+‐ATPase, also abolished the effects of trypsin (n=7). Neither trypsin (n=4) nor FLIGRL (n=4) reduced carbachol‐induced tone.In conclusion, activation of PAR‐2 inhibits spontaneous contractile activity in the rat colon via release of Ca2+ from intracellular stores and activation of SKCa channels. PAR‐2 activation is limited to pacemaker cells since no effect was observed on carbachol stimulated smooth muscle.Supported by NSERC