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Research Article

JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

¹Royal College of Surgeons in Ireland ²Beaumont Hospital

Submitted 29 May 2009 ; revision received 5 October 2009 ; accepted in final form 23 October 2009

ABSTRACT

Neuroimmune 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⁺-, but not cAMP-dependent agonists. Although c-Jun N-terminal kinase (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 T₈₄ colonic epithelial cells. Western blot analysis revealed that a prototypical Ca²⁺-dependent secretagogue, carbachol (CCh; 100 µM), induced phosphorylation of both the 46kDa and 54kDa isoforms of JNK. This effect was mimicked by thapsigargin, which specifically elevates intracellular Ca²⁺, but not by forskolin (FSK; 10 µM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 µM). Pretreatment of voltage-clamped T⁸⁴ cells with SP600125 (2 µM), 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 permeabilised T₈₄ 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.

epithelium; ion transport; chloride secretion; colon