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

Hdl Handle:
http://hdl.handle.net/10147/127233
Title:
JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.
Authors:
Donnellan, Fergal; Keating, Niamh; Geoghegan, Paul; Murray, Frank E; Harvey, Brian J P; Keely, Stephen J
Affiliation:
Dept. of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Education and Research Ctr., Smurfit Bldg., Beaumont Hospital, Dublin 9, Ireland.
Citation:
JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells. 2010, 298 (1):G37-44 Am. J. Physiol. Gastrointest. Liver Physiol.
Journal:
American journal of physiology. Gastrointestinal and liver physiology
Issue Date:
Jan-2010
URI:
http://hdl.handle.net/10147/127233
DOI:
10.1152/ajpgi.00202.2009
PubMed ID:
19875701
Additional Links:
http://ajpgi.physiology.org/content/298/1/G37.full.pdf+html
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.
Item Type:
Article
Language:
en
MeSH:
Amino Acids, Cyclic; Anthracenes; Calcium; Carbachol; Cell Line; Cell Polarity; Chlorides; Cholinergic Agonists; Colon; Enzyme Inhibitors; Epithelial Cells; Flavonoids; Humans; Intestinal Mucosa; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Phosphorylation; Potassium; Thapsigargin; Tyrphostins
ISSN:
1522-1547

Full metadata record

DC FieldValue Language
dc.contributor.authorDonnellan, Fergalen
dc.contributor.authorKeating, Niamhen
dc.contributor.authorGeoghegan, Paulen
dc.contributor.authorMurray, Frank Een
dc.contributor.authorHarvey, Brian J Pen
dc.contributor.authorKeely, Stephen Jen
dc.date.accessioned2011-04-05T14:42:28Z-
dc.date.available2011-04-05T14:42:28Z-
dc.date.issued2010-01-
dc.identifier.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.en
dc.identifier.issn1522-1547-
dc.identifier.pmid19875701-
dc.identifier.doi10.1152/ajpgi.00202.2009-
dc.identifier.urihttp://hdl.handle.net/10147/127233-
dc.description.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.-
dc.language.isoenen
dc.relation.urlhttp://ajpgi.physiology.org/content/298/1/G37.full.pdf+htmlen
dc.subject.meshAmino Acids, Cyclic-
dc.subject.meshAnthracenes-
dc.subject.meshCalcium-
dc.subject.meshCarbachol-
dc.subject.meshCell Line-
dc.subject.meshCell Polarity-
dc.subject.meshChlorides-
dc.subject.meshCholinergic Agonists-
dc.subject.meshColon-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshEpithelial Cells-
dc.subject.meshFlavonoids-
dc.subject.meshHumans-
dc.subject.meshIntestinal Mucosa-
dc.subject.meshJNK Mitogen-Activated Protein Kinases-
dc.subject.meshMAP Kinase Signaling System-
dc.subject.meshPhosphorylation-
dc.subject.meshPotassium-
dc.subject.meshThapsigargin-
dc.subject.meshTyrphostins-
dc.titleJNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.en
dc.typeArticleen
dc.contributor.departmentDept. of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Education and Research Ctr., Smurfit Bldg., Beaumont Hospital, Dublin 9, Ireland.en
dc.identifier.journalAmerican journal of physiology. Gastrointestinal and liver physiologyen
dc.description.provinceLeinster-
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