Gastrointestinal roles for proteinase-activated receptors in health and disease

Abstract

It has been almost a decade since the molecular cloning of all four members of the proteinase-activated receptor (PAR) family was completed. This unique family of G protein-coupled receptors (GPCRs) mediates specific cellular actions of various endogenous proteinases including thrombin, trypsin, tryptase, etc. and also certain exogenous enzymes. Increasing evidence has been clarifying the emerging roles played by PARs in health and disease. PARs, particularly PAR1 and PAR2, are distributed throughout the gastrointestinal (GI) tract, modulating various GI functions. One of the most important GI functions of PARs is regulation of exocrine secretion in the salivary glands, pancreas and GI mucosal epithelium. PARs also modulate motility of GI smooth muscle, involving multiple mechanisms. PAR2 appears to play dual roles in pancreatitis and related pain, being pro-inflammatory/pro-nociceptive and anti-inflammatory/anti-nociceptive. Similarly, dual roles for PAR1 and PAR2 have been demonstrated in mucosal inflammation/damage throughout the GI tract. There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases.

Figure 1

The role of PAR2 in exocrine secretion. It is of note that functions of PAR2 shown here have not necessarily been demonstrated in humans. NKA, neurokinin A; NK₂, neurokinin NK₂ receptor; CGRP₁, CGRP₁ receptor; PAR, proteinase-activated receptor.

Figure 2

Mechanisms for regulation of GI smooth muscle motility by PARs. [Ca²⁺]_in, intracellular (cytosolic) Ca²⁺ concentration; NKs, neurokinins; PGs, prostaglandins; NK₂, neurokinin NK₂ receptor; G, G protein; GI, gastrointestinal.

Figure 3

Signal transduction for PAR1-triggered prostaglandin E₂ formation in RGM1 cells. HB-EGF, heparin-binding EGF; AA, arachidonic acid; G, G protein; PGE₂, prostaglandin E₂.

Figure 4

A scheme for roles of PAR2 expressed on sensory neurons and acinar cells during pancreatitis. Trypsin, released from acinar cells in response to cytotoxic stimulation such as caerulein, causes pancreatic cell damage by proteolytic digestion, and would also activate neuronal PAR2, leading to pancreatic pain. In the early stages of pancreatitis, trypsin could activate PAR2 on the acinar cells and decrease intrapancreatic trypsin levels by stimulating exocrine secretion of trypsinogen into the duodenum, limiting the extent of pancreatitis and related pain. Unknown non-PAR2 receptors on sensory neurons should mediate pancreatic pain in response to trypsin and/or unknown nociceptive mediators, derived from acinar cells, particularly in PAR2-knockout mice.