Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2

J Clin Invest. 1999 Jan;103(2):261-9. doi: 10.1172/JCI2539.


Proteinase-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved by trypsin within the NH2-terminus, exposing a tethered ligand that binds and activates the receptor. We examined the secretory effects of trypsin, mediated through PAR-2, on well-differentiated nontransformed dog pancreatic duct epithelial cells (PDEC). Trypsin and activating peptide (AP or SLIGRL-NH2, corresponding to the PAR-2 tethered ligand) stimulated both an 125I- efflux inhibited by Ca2+-activated Cl- channel inhibitors and a 86Rb+ efflux inhibited by a Ca2+-activated K+ channel inhibitor. The reverse peptide (LRGILS-NH2) and inhibited trypsin were inactive. Thrombin had no effect, suggesting absence of PAR-1, PAR-3, or PAR-4. In Ussing chambers, trypsin and AP stimulated a short-circuit current from the basolateral, but not apical, surface of PDEC monolayers. In monolayers permeabilized basolaterally or apically with nystatin, AP activated apical Cl- and basolateral K+ conductances. PAR-2 agonists increased [Ca2+]i in PDEC, and the calcium chelator BAPTA inhibited the secretory effects of AP. PAR-2 expression on dog pancreatic ducts and PDEC was verified by immunofluorescence. Thus, trypsin interacts with basolateral PAR-2 to increase [Ca2+]i and activate ion channels in PDEC. In pancreatitis, when trypsinogen is prematurely activated, PAR-2-mediated ductal secretion may promote clearance of toxins and debris.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Dogs
  • Fluorescent Antibody Technique
  • Iodine Radioisotopes / metabolism
  • Ion Channels / metabolism*
  • Ion Transport / drug effects
  • Oligopeptides / pharmacology
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / metabolism*
  • Peptides / pharmacology
  • Receptor, PAR-2
  • Receptors, Thrombin / agonists
  • Receptors, Thrombin / metabolism*
  • Rubidium Radioisotopes / metabolism
  • Signal Transduction / physiology
  • Thrombin / pharmacology
  • Trypsin / pharmacology*


  • Iodine Radioisotopes
  • Ion Channels
  • Oligopeptides
  • Peptides
  • Receptor, PAR-2
  • Receptors, Thrombin
  • Rubidium Radioisotopes
  • seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
  • Trypsin
  • Thrombin
  • Calcium