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Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2
Toan D. Nguyen, … , Duk-Su Koh, Nigel W. Bunnett
Toan D. Nguyen, … , Duk-Su Koh, Nigel W. Bunnett
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):261-269. https://doi.org/10.1172/JCI2539.
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Article

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

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Abstract

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.

Authors

Toan D. Nguyen, Mark W. Moody, Martin Steinhoff, Charles Okolo, Duk-Su Koh, Nigel W. Bunnett

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Figure 1

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Stimulation of 125I– efflux by trypsin. 125I– efflux was monitored as de...
Stimulation of 125I– efflux by trypsin. 125I– efflux was monitored as detailed in Methods and the efflux rate coefficient shown (means ± SEM, n = 3). (a) After 1 min for baseline determination, trypsin was added at the final concentrations shown. (b) After 1 min, 1 μM of either thrombin (open circle), the PAR-1 agonist, AF(PF)RChaCitY-NH2 (PAR-1 A, open circle), or the PAR-2 agonist, tc-LGRLO-NH2 (PAR-2 A, filled circle), was added.

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