PMID- 19875701
OWN - NLM
STAT- MEDLINE
DCOM- 20100909
LR  - 20181201
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Linking)
VI  - 298
IP  - 1
DP  - 2010 Jan
TI  - JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion 
      across colonic epithelial cells.
PG  - G37-44
LID - 10.1152/ajpgi.00202.2009 [doi]
AB  - 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.
FAU - Donnellan, Fergal
AU  - Donnellan F
AD  - Dept. of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Education 
      and Research Ctr., Smurfit Bldg., Beaumont Hospital, Dublin 9, Ireland.
FAU - Keating, Niamh
AU  - Keating N
FAU - Geoghegan, Paul
AU  - Geoghegan P
FAU - Murray, Frank E
AU  - Murray FE
FAU - Harvey, Brian J P
AU  - Harvey BJ
FAU - Keely, Stephen J
AU  - Keely SJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091029
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Amino Acids, Cyclic)
RN  - 0 (Anthracenes)
RN  - 0 (Chlorides)
RN  - 0 (Cholinergic Agonists)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Quinazolines)
RN  - 0 (Tyrphostins)
RN  - 170449-18-0 (RTKI cpd)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - 67526-95-8 (Thapsigargin)
RN  - 8Y164V895Y (Carbachol)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - RWP5GA015D (Potassium)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Amino Acids, Cyclic/metabolism
MH  - Anthracenes/pharmacology
MH  - Calcium/*metabolism
MH  - Carbachol/pharmacology
MH  - Cell Line
MH  - Cell Polarity/physiology
MH  - Chlorides/*metabolism
MH  - Cholinergic Agonists/pharmacology
MH  - Colon/cytology/*enzymology
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/cytology/drug effects/enzymology
MH  - Flavonoids/pharmacology
MH  - Humans
MH  - Intestinal Mucosa/cytology/*enzymology
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - MAP Kinase Signaling System/drug effects/*physiology
MH  - Phosphorylation/drug effects/physiology
MH  - Potassium/metabolism
MH  - Quinazolines
MH  - Thapsigargin/pharmacology
MH  - Tyrphostins/pharmacology
EDAT- 2009/10/31 06:00
MHDA- 2010/09/10 06:00
CRDT- 2009/10/31 06:00
PHST- 2009/10/31 06:00 [entrez]
PHST- 2009/10/31 06:00 [pubmed]
PHST- 2010/09/10 06:00 [medline]
AID - ajpgi.00202.2009 [pii]
AID - 10.1152/ajpgi.00202.2009 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2010 Jan;298(1):G37-44. doi: 
      10.1152/ajpgi.00202.2009. Epub 2009 Oct 29.