Journal Article


Stephen J Keely
Brian J P Harvey
Frank E Murray
Paul Geoghegan
Niamh Keating
Fergal Donnellan



metabolism quinazolines jnk mitogen activated protein kinases calcium anthra 1 9 cd pyrazol 6 tyrphostin ag 1478 thapsigargin amino acids cyclic chlorides phosphorylation physiology pharmacology colon potassium map kinase signaling system cell polarity epithelial cells enzyme inhibitors intestinal mucosa tyrphostins enzymology cholinergic agonists carbachol anthracenes cell line pd 98059 flavonoids cytology drug effects humans

JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells. (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+-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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Stephen J Keely, Brian J P Harvey, Frank E Murray, Paul Geoghegan, Niamh Keating, Fergal Donnellan

Experts in our system

Stephen J Keely
Royal College of Surgeons in Ireland
Total Publications: 31
Brian J Harvey
Royal College of Surgeons in Ireland
Total Publications: 102
F E Murray
Royal College of Surgeons in Ireland