JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.
Murray, Frank E
Harvey, Brian J P
Keely, Stephen J
AffiliationDept. of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Education and Research Ctr., Smurfit Bldg., Beaumont Hospital, Dublin 9, Ireland.
MeSHAmino Acids, Cyclic
JNK Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
MetadataShow full item record
CitationJNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells. 2010, 298 (1):G37-44 Am. J. Physiol. Gastrointest. Liver Physiol.
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
AbstractNeuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.
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