Protease-activated receptors: novel central role in modulation of gastric functions.

Protease-activated receptors (PARs) are members of a subfamily of G-protein-coupled receptors that regulate diverse cell functions in response to proteolytic cleavage of an anchored peptide domain that acts as a 'tethered' receptor-activating ligand. PAR-1 and PAR-2 in particular are present throughout the gastrointestinal (GI) tract and play prominent roles in the regulation of GI epithelial function, motility, inflammation and nociception. In a recent article in Neurogastroenterology and Motility, Wang et al. demonstrate, for the first time, that PAR-1 and PAR-2 are present on preganglionic parasympathetic neurons within the rat brainstem. As in other cellular systems, proteases such as thrombin and trypsin activate PAR-1 and PAR-2 on neurons of the dorsal motor nucleus of the vagus (DMV), leading to an increase in intracellular calcium levels via signal transduction mechanisms involving activation of phospholipase C and inositol triphosphate (IP3). The authors also report that the level of PAR-1 and PAR-2 transcripts in DMV tissue is increased following experimental colitis, suggesting that inflammatory conditions may modulate neuronal behavior or induce plasticity within central vagal neurocircuits. It seems reasonable to hypothesize, therefore, that the activity and behavior of vagal efferent motoneurons may be modulated directly by local and/or systemic proteases released during inflammation. This, in turn, may contribute to the increased incidence of functional GI disorders, including gastric dysmotility, delayed emptying and gastritis observed in patients with inflammatory bowel diseases.