Review article: proteinase-activated receptors - novel signals for gastrointestinal pathophysiology

Aliment Pharmacol Ther. 2000 Mar;14(3):257-66. doi: 10.1046/j.1365-2036.2000.00690.x.

Abstract

Proteinase-activated receptors (PARs) have the common property of being activated by the proteolytic cleavage of their extracellular N-terminal domain. The new NH2-terminus acts as a 'tethered ligand' binding and activating the receptor itself. Four members of this family have been cloned, three of which are activated by thrombin (PAR-1, PAR-3 and PAR-4) while the fourth (PAR-2) is activated by trypsin or mast cell tryptase. In physiological or pathophysiological conditions, the gastrointestinal tract is exposed more than other tissues to proteinases (digestive enzymes, proteinases from pathogens or proteinases from inflammatory cells) that can activate PARs. Since PARs are highly expressed throughout the gastrointestinal tract, the study of the role of PARs in these tissues appears to be particularly important. It has already been shown that PAR-2 activation induces calcium mobilization and eicosanoid production in enterocytes as well as changes in ion transport in jejunal tissue segments. PAR-2 activation also causes calcium mobilization and stimulates amylase release from pancreatic acini. Moreover, both PAR-1 and PAR-2 activation can alter the gastrointestinal motility. In inflammatory or allergic conditions, the proteinases that constitute the major agonists for PARs (thrombin, trypsin and mast cell tryptase) are usually released. The activation of PARs by these proteinases might contribute to the gastrointestinal disorders associated with these pathologies. A complete understanding of the role of PARs in the gastrointestinal tract will require the development of selective receptor antagonists that are not yet available. Nonetheless, the use of PAR agonists has already highlighted new potential functions for proteinases in the gastrointestinal tract, thus the control of PAR activation might represent a promising therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Digestive System / physiopathology*
  • Humans
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Thrombin / chemistry
  • Receptors, Thrombin / physiology*

Substances

  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Thrombin
  • protease-activated receptor 3
  • protease-activated receptor 4