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Effects of transient receptor potential channel blockers on pacemaker activity in interstitial cells of Cajal from mouse small intestine

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Molecules and Cells

Abstract

The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract and transient receptor potential melastatin type 7 (TRPM7) is a candidate for pacemaker channels. The effect of the 5-lipoxygenase (5-LOX) inhibitors NDGA, AA861, MK886 and zileuton on pacemaking activity of ICCs was examined using the whole cell patch clamp technique. NDGA and AA861 decreased the amplitude of pacemaker potentials in ICC clusters, but the resting membrane potentials displayed little change, respectively. Also, perfusing NDGA and AA861 into the bath reduced both inward current and outward current in TRPM7-like current in single ICC, respectively. But, they had no effects on Ca2+ activated Cl currents. The 5-LOX inhibitors MK886 and zileuton were, however, ineffective in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC, respectively. A specific TRPC3 inhibitor, pyrazole compound (Pyr3), and a specific TRPM4 inhibitor, 9-phenanthrol, had no effects in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC. These results suggest that, among the tested 5-LOX inhibitors, NDGA and AA861 modulate the pacemaker activities of the ICCs, and that the TRPM7 channel can affect intestinal motility.

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References

  • Aarts, M., Iihara, K., Wei, W.L., Xiong, Z.G., Arundine, M., Cerwinski, W., MacDonald, J.F., and Tymianski, M. (2003). A key role for TRPM7 channels in anoxic neuronal death. Cell 115, 863–877.

    Article  PubMed  CAS  Google Scholar 

  • Abed, E., and Moreau, R. (2009). Importance of melastatin-like transient receptor potential 7 and magnesium in the stimulation of osteoblast proliferation and migration by platelet derived growth factor. Am. J. Physiol. Cell. Physiol. 297, C360–C368.

    Article  PubMed  CAS  Google Scholar 

  • Brauchi, S., Krapivinsky, G., Krapivinsky, L., and Clapham, D.E. (2008). TRPM7 facilitates cholinergic vesicle fusion with the plasma membrane. Proc. Natl. Acad. Sci. USA 105, 8304–8308.

    Article  PubMed  CAS  Google Scholar 

  • Chen, H.C., Xie, J., Zhang, Z., Su, L.T., Yue, L., and Runnels, L.W. (2010). Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. PLoS One 5, e11161.

    Article  PubMed  Google Scholar 

  • Clapham, D.E. (2003). TRP channels as cellular sensors. Nature 426, 517–524.

    Article  PubMed  CAS  Google Scholar 

  • Dickens, E.J., Hirst, G.D., and Tomita, T. (1999). Identification of rhythmically active cells in guinea-pig stomach. J. Physiol. 514, 515–531.

    Article  PubMed  CAS  Google Scholar 

  • Elizondo, M.R., Arduini, B.L., Paulsen, J., MacDonald, E.L., Sabel, J.L., Henion, P.D., Cornell, R.A., and Parichy, D.M. (2005). Defective skeletogenesis with kidney stone formation in dwarf zebrafish mutant for trpm7. Curr. Biol. 15, 667–671.

    Article  PubMed  CAS  Google Scholar 

  • Guilbert, A., Gautier, M., Dhennin-Duthille, I., Haren, N., Sevestre, H., and Ouadid-Ahidouch, H. (2009). Evidence that TRPM7 is required for breast cancer cell proliferation. Am. J. Physiol. Cell. Physiol. 297, C493–C502.

    Article  PubMed  CAS  Google Scholar 

  • Huizinga, J.D., Thuneberg, L., Kluppel, M., Malysz, J., Mikkelsen, H.B., and Bernstein, A. (1995). W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373, 347–349.

    Article  PubMed  CAS  Google Scholar 

  • Huizinga, J.D., Thuneberg, L., Vanderwinden, J.M., and Rumessen, J.J. (1997). Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders. Trends Pharmacol. Sci. 18, 393–403.

    PubMed  CAS  Google Scholar 

  • Huizinga, J.D., Zhu, Y., Ye, J., and Molleman, A. (2002). Highconductance chloride channels generate pacemaker currents in interstitial cells of Cajal. Gastroenterology 123, 1627–1636.

    Article  PubMed  CAS  Google Scholar 

  • Kim, B.J., Lim, H.H., Yang, D.K., Jun, J.Y., Chang, I.Y., Park, C.S., So, I., Stanfield, P.R., and Kim, K.W. (2005). Melastatin-type transient receptor potential channel 7 is required for intestinal pacemaking activity. Gastroenterology 129, 1504–1517.

    Article  PubMed  CAS  Google Scholar 

  • Kim, B.J., Park, E.J., Lee, J.H., Jeon, J.H., Kim, S.J., and So, I. (2008). Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci. 99, 2502–2509.

    Article  PubMed  CAS  Google Scholar 

  • Koh, S.D., Jun, J.Y., Kim, T.W., and Sanders, K.M. (2002). A Ca2+-inhibited nonselective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal. J. Physiol. 540, 803–814.

    Article  PubMed  CAS  Google Scholar 

  • Komuro, T., Seki, K., and Horiguchi, K. (1999). Ultrastructural characterization of the interstitial cells of Cajal. Arch. Histol. Cytol. 62, 295–316.

    Article  PubMed  CAS  Google Scholar 

  • Langton, P., Ward, S.M., Carl, A., Norell, M.A., and Sanders, K.M. (1989). Spontaneous electrical activity of interstitial cells of Cajal isolated from canine proximal colon. Proc. Natl. Acad. Sci. USA 86, 7280–7284.

    Article  PubMed  CAS  Google Scholar 

  • Maeda, H., Yamagata, A., Nishikawa, S., Yoshinaga, K., Kobayashi, S., Nishi, K., and Nishikawa, S. (1992). Requirement of c-kit for development of intestinal pacemaker system. Development 116, 369–375.

    PubMed  CAS  Google Scholar 

  • Mazzone, A., Bernard, C.E., Strege, P.R., Beyder, A., Galietta, L.J., Pasricha, P.J., Rae, J.L., Parkman, H.P., Linden, D.R., Szurszewski, J.H., et al. (2011). Altered expression of ano1 variants in human diabetic gastroparesis. J. Biol. Chem. 286, 13393–13403.

    Article  PubMed  CAS  Google Scholar 

  • Nadler, M.J.S., Hermosura, M.C., Inabe, K., Perraud, A.L., Zhu, Q., Stokes, A.J., Kurosaki, T., Kinet, J.P., Penner, R., Scharenberg, A.M., et al. (2001). LTRPC7 is a MgNATP-regulated divalent cation channel required for cell viability. Nature 411, 590–595.

    Article  PubMed  CAS  Google Scholar 

  • Ordog, T., Ward, S.M., and Sanders, K.M. (1999). Interstitial cells of cajal generate electrical slow waves in the murine stomach. J. Physiol. 518, 257–269.

    Article  PubMed  CAS  Google Scholar 

  • Peters-Golden, M., and Brock, T.G. (2003). 5-lipoxygenase and FLAP. Prostaglandins Leukot. Essent. Fatty Acids 69, 99–109.

    Article  CAS  Google Scholar 

  • Runnels, L.W., Yue, L., and Clapham, D.E. (2001). TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291, 1043–1047.

    Article  PubMed  CAS  Google Scholar 

  • Sahni, J., and Scharenberg, A.M. (2008). TRPM7 ion channels are required for sustained phosphoinositide 3-kinase signaling in lymphocytes. Cell. Metab. 8, 84–93.

    Article  PubMed  CAS  Google Scholar 

  • Sanders, K.M. (1996). A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111, 492–515.

    Article  PubMed  CAS  Google Scholar 

  • Sanders, K.M., Ordog, T., Koh, S.D., Torihashi, S., and Ward, S.M. (1999). Development and plasticity of interstitial cells of Cajal. Neurogastroenterol. Motil. 11, 311–338.

    Article  PubMed  CAS  Google Scholar 

  • Schmitz, C., Perraud, A.L., Johnson, C.O., Inabe, K., Smith, M.K., Penner, R., Kurosaki, T., Fleig, A., and Scharenberg, A.M. (2003). Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 114, 191–200.

    Article  PubMed  CAS  Google Scholar 

  • Tomita, T. (1981). Electrical activity (spikes and slow wave) in gastrointestinal smooth muscles. E. Bulbring, A.F. Brading, A.W. Jones, and T. Tomita, eds. (London, UK: Edward Arnold), pp. 127–156.

    Google Scholar 

  • Torihashi, S., Ward, S.M., Nishikawa, S., Nishi, K., Kobayashi, S., and Sanders, K.M. (1995). c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res. 280, 97–111.

    PubMed  CAS  Google Scholar 

  • Vriens, J., Owsianik, G., Voets, T., Droogmans, G., and Nilius, B. (2004). Invertebrate TRP proteins as functional models for mammalian channels. Pflugers Arch. 449, 213–226.

    PubMed  CAS  Google Scholar 

  • Ward, S.M., Burns, A.J., Torihashi, S., and Sanders, K.M. (1994). Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J. Physiol. 480, 91–97.

    PubMed  CAS  Google Scholar 

  • Werz, O. (2002). 5-lipoxygenase: cellular biology and molecular pharmacology. Curr. Drug. Targets Inflamm. Allergy 1, 23–44.

    Article  PubMed  CAS  Google Scholar 

  • Yoo, S., Han, S., Park, Y.S., Lee, J.H., Oh, U., and Hwang, S.W. (2009). Lipoxygenase inhibitors suppressed carrageenan-induced Fos-expression and inflammatory pain responses in the rat. Mol. Cells 27, 417–422.

    Article  PubMed  CAS  Google Scholar 

  • Yoshimoto, T., Yokoyama, C., Ochi, K., Yamamoto, S., Maki, Y., Ashida, Y., Terao, S., and Shiraishi, M. (1982). 2,3,5-Trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861), a selective inhibitor of the 5-lipoxygenase reaction and the biosynthesis of slow reacting substance of anaphylaxis. Biochim. Biophys. Acta 713, 470–473.

    PubMed  CAS  Google Scholar 

  • Zhu, M.H., Kim, T.W., Ro, S., Yan, W., Ward, S.M., Koh, S.D., and Sanders, K.M. (2009). A Ca2+-activated Cl conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J. Physiol. 587, 4905–4918.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Seon Jeong Kim.

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Kim, B.J., Nam, J.H. & Kim, S.J. Effects of transient receptor potential channel blockers on pacemaker activity in interstitial cells of Cajal from mouse small intestine. Mol Cells 32, 153–160 (2011). https://doi.org/10.1007/s10059-011-1019-1

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  • DOI: https://doi.org/10.1007/s10059-011-1019-1

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