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Am J Physiol Cell Physiol. 2003 Feb;284(2):C339-48. Epub 2002 Oct 3.

p38 mitogen-activated protein kinase inhibits calcium-dependent chloride secretion in T84 colonic epithelial cells.

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  • 1Department of Medicine, University of California, San Diego, California 92103, USA. skeely@ucsd.edu

Abstract

We have previously shown that Ca(2+)-dependent Cl(-) secretion across intestinal epithelial cells is limited by a signaling pathway involving transactivation of the epidermal growth factor receptor (EGFR) and activation of ERK mitogen-activated protein kinase (MAPK). Here, we have investigated a possible role for p38 MAPK in regulation of Ca(2+)-dependent Cl(-) secretion. Western blot analysis of T(84) colonic epithelial cells revealed that the muscarinic agonist carbachol (CCh; 100 microM) stimulated phosphorylation and activation of p38 MAPK. The p38 inhibitor SB-203580 (10 microM) potentiated and prolonged short-circuit current (I(sc)) responses to CCh across voltage-clamped T(84) 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 AG-1478 (0.1 nM-10 microM) and by the Src family kinase inhibitor PP2 (20 nM-2 microM). The effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 microM), which specifically elevates intracellular Ca(2+), and were abolished by the Ca(2+) chelator BAPTA-AM (20 microM), implying a role for intracellular Ca(2+) in mediating p38 activation. SB-203580 (10 microM) potentiated I(sc) responses to TG to 172.4 +/- 18.1% of those in control cells (n = 18; P < 0.001). When cells were pretreated with SB-203580 and PD-98059 to simultaneously inhibit p38 and ERK MAPKs, respectively, I(sc) responses to TG and CCh were significantly greater than those observed with either inhibitor alone. We conclude that Ca(2+)-dependent agonists stimulate p38 MAPK in T(84) cells by a mechanism involving intracellular Ca(2+), 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.

PMID:
12388102
DOI:
10.1152/ajpcell.00144.2002
[PubMed - indexed for MEDLINE]
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