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1 Universitäts-Kinderklinik, Albert-Ludwigs-Universität Freiburg, 79106 Freiburg, Germany; and 2 Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Queensland 4072, Brisbane, Australia
Proteinase-activated receptor (PAR) type 2 (PAR-2) has been shown to mediate ion secretion in cultured epithelial
cells and rat jejunum. With the use of a microUssing chamber, we
demonstrate the role of PAR-2 for ion transport in native human colonic
mucosa obtained from 30 normal individuals and 11 cystic fibrosis (CF) patients. Trypsin induced Cl
secretion when added to the
basolateral but not luminal side of normal epithelia. Activation of
Cl secretion by trypsin was inhibited by indomethacin and
was further increased by cAMP in normal tissues but was not present in
CF colon, indicating the requirement of luminal CF transmembrane conductance regulator. Effects of trypsin were largely reduced by low Cl, by basolateral bumetanide, and in the presence
of barium or clotrimazole, but not by tetrodotoxin. Furthermore,
trypsin-induced secretion was inhibited by the Ca2+-ATPase
inhibitor cyclopiazonic acid and in low-Ca2+ buffer. The
effects of trypsin were almost abolished by trypsin inhibitor.
Thrombin, an activator of PAR types 1, 3, and 4, had no effects on
equivalent short-circuit currents. The presence of PAR-2 in human colon
epithelium was confirmed by RT-PCR and additional experiments with
PAR-2-activating peptide. PAR-2-mediated intestinal electrolyte
secretion by release of mast cell tryptase and potentiation of PAR-2
expression by tumor necrosis factor-
may contribute to the
hypersecretion observed in inflammatory processes such as chronic
inflammatory bowel disease.
protease-activated receptors; ion transport; trypsin; cystic fibrosis transmembrane conductance regulator; inflammatory bowel disease
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