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Am J Physiol Cell Physiol 284: C339-C348, 2003. First published October 3, 2002; doi:10.1152/ajpcell.00144.2002
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Vol. 284, Issue 2, C339-C348, February 2003

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

Stephen J. Keely and Kim E. Barrett

Department of Medicine, University of California, San Diego, California 92103

We have previously shown that Ca2+-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 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 SB-203580 (10 µM) potentiated and prolonged short-circuit current (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 AG-1478 (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. SB-203580 (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 SB-203580 and PD-98059 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.

G protein-coupled receptor; epidermal growth factor receptor; intestinal secretion


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