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Effects of Ca2+-Activated Cl- Channel ANO1inhibitors on Pacemaker Activity in Interstitial Cells of Cajal

Authors
  • Choi, Seok
  • Kang, Hyun Goo
  • Wu, Mei Jin
  • Jiao, Han Yi
  • Shin, Dong Hoon
  • Hong, Chansik
  • Jun, Jae Yeoul
Type
Published Article
Journal
Cellular Physiology and Biochemistry
Publisher
S. Karger AG
Publication Date
Dec 14, 2018
Volume
51
Issue
6
Pages
2887–2899
Identifiers
DOI: 10.1159/000496041
PMID: 30562749
Source
Karger
Keywords
License
Green
External links

Abstract

Background/Aims: Anoctamin1 (Ca2+-activated Cl- channel, ANO1) is a specific marker of the interstitial cells of Cajal (ICC) in the gastrointestinal tract, and are candidate proteins that can function as pacemaker channels. Recently, novel selective ANO1 inhibitors were discovered and used to study Ca2+-activated Cl- channels. Therefore, to investigate whether ANO1 channels function as pacemaker channels, selective ANO1 inhibitors were tested with respect to the pacemaker potentials in ICC. Methods: Whole-cell patch-clamp recording, RT-PCR, and intracellular Ca2+ ([Ca2+]i) imaging were performed in cultured ICC obtained from mice. Results: Though CaCCinh-A01 (5 µM), T16Ainh-A01 (5 µM), and MONNA (5 µM) (selective ANO1 inhibitors) blocked the generation of pacemaker potentials in colonic ICC, they did not do so in small intestinal ICC. Though nifulmic acid (10 µM) and DIDS (10 µM) (classical Ca2+-activated Cl- channel inhibitors) also had no effect in small intestinal ICC, they suppressed the generation of pacemaker potentials in colonic ICC. In addition, knockdown of ANO1 reduced the pacemaker potential frequency in colonic ICC alone. Though ANO1 inhibitors suppressed [Ca2+]i oscillations in colonic ICC, they did not do so in small intestinal ICC. T-type Ca2+ channels were expressed in the both the small intestinal and colonic ICC, but mibefradil (5 µM) and NiCl2 (30 µM) (T-type Ca2+ channel inhibitors) inhibited the generation of pacemaker potentials in colonic ICC alone. Conclusion: These results indicate that though ANO1 and T-type Ca2+ channels participate in generating pacemaker potentials in colonic ICC, they do not do so in small intestinal ICC. Therefore, the mechanisms underlying pacemaking in ICC might be different in the small intestine and the colon.

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