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secretion in human
intestinal epithelial cells
Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1
The thrombin receptor, protease-activated receptor-1
(PAR-1), has wide tissue distribution and is involved
in many physiological functions. Because thrombin is in the intestinal
lumen and mucosa during inflammation, we sought to determine PAR-1
expression and function in human intestinal epithelial cells. RT-PCR
showed PAR-1 mRNA expression in SCBN cells, a nontransformed duodenal
epithelial cell line. Confluent SCBN monolayers mounted in Ussing
chambers responded to PAR-1 activation with a
Cl
-dependent increase in short-circuit current. The
secretory effect was blocked by BaCl2 and the
Ca2+-ATPase inhibitor thapsigargin, but not by the L-type
Ca2+ channel blocker verapamil or DIDS, the nonselective
inhibitor of Ca2+-dependent Cl transport.
Responses to thrombin and PAR-1-activating peptides exhibited auto- and
crossdesensitization. Fura 2-loaded SCBN cells had increased
fluorescence after PAR-1 activation, indicating increased intracellular
Ca2+. RT-PCR showed that SCBN cells expressed mRNA for the
cystic fibrosis transmembrane conductance regulator (CFTR) and
hypotonicity-activated Cl channel-2 but not for the
Ca2+-dependent Cl channel-1. PAR-1 activation
failed to increase intracellular cAMP, suggesting that the CFTR channel
is not involved in the Cl secretory response. Our data
demonstrate that PAR-1 is expressed on human intestinal epithelial
cells and regulates a novel Ca2+-dependent Cl
secretory pathway. This may be of clinical significance in inflammatory intestinal diseases with elevated thrombin levels.
thrombin; epithelium; ion transport; serine endopeptidases; chloride channels
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