Receptor tyrosine and MAP kinase are involved in effects of  H(2)O(2) on interstitial cells of Cajal in murine intestine.
Hydrogen peroxide (H(2)O(2)) is involved in intestinal motility through changes of smooth muscle activity. However, there is no report as to the modulatory effects of H(2)O(2) on interstitial cells of Cajal (ICC). We investigated the H(2)O(2) effects and signal transductions to determine whether the intestinal motility can be modulated through ICC. We performed whole-cell patch clamp in cultured ICC from murine intestine and molecular analyses. H(2)O(2) hyperpolarized the membrane and inhibited pacemaker currents. These effects were inhibited by glibenclamide, an inhibitor of ATP-sensitive K+ (K(ATP)) channels. The free-radical scavenger catalase inhibited the H(2)O(2)-induced effects. MAFP and AACOCF3 (a cytosolic phospholipase A2 inhibitors) or SC-560 and NS-398 (a selective COX-1 and 2 inhibitor) or AH6809 (an EP2 receptor antagonist) inhibited the H(2)O(2)-induced effects. PD98059 (a mitogen activated/ERK-activating protein kinase inhibitor) inhibited the H(2)O(2)-induced effects, though SB-203580 (a p38 MAPK inhibitor) or a JNK inhibitor did not affect. H(2)O(2)-induced effects could not be inhibited by LY-294002 (an inhibitor of PI3-kinases), calphostin C (a protein kinase C inhibitor) or SQ-22536 (an adenylate cyclase inhibitor). Adenoviral infection analysis revealed H2O2 stimulated tyrosine kinase activity and AG 1478 (an antagonist of epidermal growth factor receptor tyrosine kinase) inhibited the H(2)O(2)-induced effects. These results suggest H(2)O(2) can modulate ICC pacemaker activity and this occur by the activation of K(ATP) channels through PGE(2) production via receptor tyrosine kinase-dependent MAP kinase activation.
Choi
Seok
S
Department of Physiology, College of Medicine, Chosun University, Gwangju, Korea.
Yeum
Cheol Ho
CH
Kim
Young Dae
YD
Park
Chan Guk
CG
Kim
Man Yoo
MY
Park
Jong-Seong
JS
Jeong
Han-Seong
HS
Kim
Byung Joo
BJ
So
Insuk
I
Kim
Ki Whan
KW
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D056885:Interstitial Cells of Cajal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D007422:Intestines / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D054467:Phospholipases A2 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D016877:Oxidants; D006861:Hydrogen Peroxide; D002374:Catalase; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D054467:Phospholipases A2