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Articles in PresS, published online ahead of print October 2, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00144.2002
Submitted on April 1, 2002
Accepted on September 28, 2002
1 Medicine, University of California, San Diego, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: skeely{at}ucsd.edu.
We have previously shown that Ca2+-dependent Cl- secretion across intestinal epithelial cells is limited by a signaling pathway involving transactivation of the EGFr and activation of ERK MAPK. Here we have investigated a possible role for p38 MAPK in regulation of Ca2+-dependent Cl- secretion. Western blot analysis of T84 colonic epithelial cells revealed that the muscarinic agonist, carbachol (CCh; 100 µM), stimulated phosphorylation and activation of p38 MAPK. The p38 inhibitor, SB203580 (10 µM), potentiated and prolonged Isc responses to CCh across voltage-clamped T84 cells to 157.4±6.9% of those in control cells (n=21; p<0.001). CCh-induced p38 phosphorylation was attenuated by the EGFr inhibitor, tyrphostin AG1478 (0.1 nM-10 µM) and by the Src family kinase inhibitor, PP2 (20 nM-2 µM). The effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 µM), which specifically elevates intracellular Ca2+, and were abolished by the Ca2+ chelator, BAPTA/AM (20 µM), implying a role for intracellular Ca2+ in mediating p38 activation. SB203580 (10 µM) potentiated Isc responses to TG to 172.4±18.1% of those in control cells (n=18; p<0.001). When cells were pretreated with SB203580 and PD98059 to simultaneously inhibit p38 and ERK MAPKs respectively, Isc responses to TG and CCh were significantly greater than those observed with either inhibitor alone. We conclude that Ca2+-dependent agonists stimulate p38 MAPK in T84 cells by a mechanism involving intracellular Ca2+, Src family kinases, and the EGFr. CCh-stimulated p38 activation constitutes a similar, but distinct and complementary, antisecretory signaling pathway to that of ERK MAPK.
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