PMID- 12388102
OWN - NLM
STAT- MEDLINE
DCOM- 20030225
LR  - 20200930
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 284
IP  - 2
DP  - 2003 Feb
TI  - p38 mitogen-activated protein kinase inhibits calcium-dependent chloride 
      secretion in T84 colonic epithelial cells.
PG  - C339-48
AB  - We have previously shown that Ca(2+)-dependent Cl(-) secretion across intestinal 
      epithelial cells is limited by a signaling pathway involving transactivation of 
      the epidermal growth factor receptor (EGFR) and activation of ERK 
      mitogen-activated protein kinase (MAPK). Here, we have investigated a possible 
      role for p38 MAPK in regulation of Ca(2+)-dependent Cl(-) secretion. Western blot 
      analysis of T(84) colonic epithelial cells revealed that the muscarinic agonist 
      carbachol (CCh; 100 microM) stimulated phosphorylation and activation of p38 
      MAPK. The p38 inhibitor SB-203580 (10 microM) potentiated and prolonged 
      short-circuit current (I(sc)) responses to CCh across voltage-clamped T(84) cells 
      to 157.4 +/- 6.9% of those in control cells (n = 21; P < 0.001). CCh-induced p38 
      phosphorylation was attenuated by the EGFR inhibitor tyrphostin AG-1478 (0.1 
      nM-10 microM) and by the Src family kinase inhibitor PP2 (20 nM-2 microM). The 
      effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 
      microM), which specifically elevates intracellular Ca(2+), and were abolished by 
      the Ca(2+) chelator BAPTA-AM (20 microM), implying a role for intracellular 
      Ca(2+) in mediating p38 activation. SB-203580 (10 microM) potentiated I(sc) 
      responses to TG to 172.4 +/- 18.1% of those in control cells (n = 18; P < 0.001). 
      When cells were pretreated with SB-203580 and PD-98059 to simultaneously inhibit 
      p38 and ERK MAPKs, respectively, I(sc) responses to TG and CCh were significantly 
      greater than those observed with either inhibitor alone. We conclude that 
      Ca(2+)-dependent agonists stimulate p38 MAPK in T(84) cells by a mechanism 
      involving intracellular Ca(2+), Src family kinases, and the EGFR. CCh-stimulated 
      p38 activation constitutes a similar, but distinct and complementary, 
      antisecretory signaling pathway to that of ERK MAPK.
FAU - Keely, Stephen J
AU  - Keely SJ
AD  - Department of Medicine, University of California, San Diego, California 92103, 
      USA. skeely@ucsd.edu
FAU - Barrett, Kim E
AU  - Barrett KE
LA  - eng
GR  - DK-28305/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021003
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Chlorides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Muscarinic Agonists)
RN  - 0 (Receptor, Muscarinic M3)
RN  - 0 (Receptors, Muscarinic)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Calcium Signaling/drug effects/*physiology
MH  - Cells, Cultured
MH  - Chlorides/*metabolism
MH  - Colon/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/drug effects/*metabolism
MH  - ErbB Receptors/agonists/metabolism
MH  - Humans
MH  - Intestinal Mucosa/*metabolism
MH  - MAP Kinase Signaling System/drug effects/physiology
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Muscarinic Agonists/pharmacology
MH  - Phosphorylation/drug effects
MH  - Protein Kinase C/drug effects/metabolism
MH  - Receptor, Muscarinic M3
MH  - Receptors, Muscarinic/drug effects/metabolism
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Water-Electrolyte Balance/drug effects/*physiology
MH  - p38 Mitogen-Activated Protein Kinases
MH  - src-Family Kinases/antagonists & inhibitors/metabolism
EDAT- 2002/10/22 04:00
MHDA- 2003/02/26 04:00
CRDT- 2002/10/22 04:00
PHST- 2002/10/22 04:00 [pubmed]
PHST- 2003/02/26 04:00 [medline]
PHST- 2002/10/22 04:00 [entrez]
AID - 00144.2002 [pii]
AID - 10.1152/ajpcell.00144.2002 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2003 Feb;284(2):C339-48. doi: 
      10.1152/ajpcell.00144.2002. Epub 2002 Oct 3.