The Role of Mitochondrial ATP-sensitive Potassium Channel on Intestinal Pacemaking Activity

  • Kim, Byung-Joo (Department of Physiology and Biophysics, Seoul National University College of Medicine) ;
  • Kim, Ki-Whan (Department of Physiology and Biophysics, Seoul National University College of Medicine)
  • Published : 2005.08.21

Abstract

Interstitial cells of Cajal (ICCs) are the pacemaker cells that generate slow waves in the gastrointestinal (GI) tract. In the present study, we investigated the effect of mitochondrial ATP-sensitive potassium (mitoKATP) channel on pacemaking activity in cultured ICCs from murine small intestine by using whole-cell patch clamp techniques. Under current clamp mode, at 10μM glibenclamide, there was no change in pacemaking activity of ICCs. At $30{\mu}M$ glibenclamide, an inhibitor of the ATP sensitive $K^+$ channels, we could find two examples. If pacemaking activity of ICCs was irregulating, pacemaking activity of ICCs was changed into regulating and if in normal conditions, membrane potential amplitude was increased. At $50{\mu}M$ glibenclamide, the resting membrane potential was depolarized. At 3mM 5-HDA, an inhibitor of the mitoKATP channels, inhibited the pacemaking activity of ICCs. Both the amplitude and the frequency were decreased. At 5 mM 5-HDA, both the amplitude and the frequency were completely abolished. Diazoxide, an opener of the mitoKATP channels, was applied to examine its effect on pacemaking activity of ICCs. At $50{\mu}M$ concentration, the pacemaking activity of ICCs was inhibited. Both the amplitude and the frequency were decreased. At 1 mM concentration, both the amplitude and the frequency were completely abolished and the resting membrane potential was shaked.These results indicate that mitoKATP channel has an important role in pacemaking activity of ICCs.

Keywords

References

  1. Ardehali H. Role of the mitochondrial ATP-sensitive $K^{+}$ channels in cardioprotection. Acta Biochim Pol 51: 379-390, 2004
  2. Cook DL, Hales CN. Intracellular ATP directly blocks $K^{+}$ channels in pancreatic $\beta$ -cells. Nature 311: 271-273, 1984 https://doi.org/10.1038/311271a0
  3. Debska G, Kicinska A, Skalska J, Szewczyk A, May R, Elger CE, Kunz WS. Opening of potassium channels modulates mitochondrial function in rat skeletal muscle. Biochim Biophys Acta 1556: 97-105, 2002 https://doi.org/10.1016/S0005-2728(02)00340-7
  4. Fukuta H, Kito Y, Suzuki H. Spontaneous electrical activity and associated changes in calcium concentration in guinea-pig gastric smooth muscle. J Physiol 540(Pt 1): 249-260, 2002 https://doi.org/10.1113/jphysiol.2001.013306
  5. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATPsensitive $K^{+}$ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072-1082, 1997 https://doi.org/10.1161/01.RES.81.6.1072
  6. Goto K, Matsuoka S, Noma A. Two types of spontaneous depolarizations in the interstitial cells freshly prepared from the murine small intestine. J Physiol 559: 411-422, 2004 https://doi.org/10.1113/jphysiol.2004.063875
  7. Grover GJ, D'Alonzo AJ, Dzwonczyk S, Parham CS, Darbenzio RB. Preconditioning is not abolished by the delayed rectifier $K^{+}$ blocker dofetilide. Am J Physiol 271: H1207-1214, 1996
  8. Grover GJ, Garlid KD. ATP-sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol 32: 677-695, 2000 https://doi.org/10.1006/jmcc.2000.1111
  9. Gross GJ, Fryer RM. Sarcolemmal versus mitochondrial ATP sensitive $K^{+}$ channels and myocardial preconditioning. Circ Res 84: 973-979, 1999 https://doi.org/10.1161/01.RES.84.9.973
  10. Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for intestinal pacemaker activity. Nature 373: 347-349, 1995. https://doi.org/10.1038/373347a0
  11. Inoue I, Nagase H, Kishi K, Higuti T. ATP-sensitive $K^{+}$ channel in the mitochondrial inner membrane. Nature 352: 244-247, 1991 https://doi.org/10.1038/352244a0
  12. Koh SD, Sanders KM, Ward SM. Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal from the murine small intestine. J Physiol 513: 203-213, 1998 https://doi.org/10.1111/j.1469-7793.1998.203by.x
  13. Langton P, Ward SM, Carl A, Norell A, Sanders KM. Spontaneous electrical activity of interstitial cells of Cajal isolated from canine proximal colon. Proc Natl Acad Sci USA 86: 7280-7284, 1989 https://doi.org/10.1073/pnas.86.18.7280
  14. Litsky ML, Pfeiffer DR. Regulation of the mitochondrial $Ca^{2+}$ uniporter by external adenine nucleotides: the uniporter behaves like a gated channel which is regulated by nucleotides and divalent cations. Biochemistry 36: 7071-7080, 1997 https://doi.org/10.1021/bi970180y
  15. McCully JD, Levitsky S. The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg 75: S667-673, 2003 https://doi.org/10.1016/S0003-4975(02)04689-1
  16. Noma A. ATP-regulated $K^{+}$ channels in cardiac muscle. Nature 305: 147-148, 1983 https://doi.org/10.1038/305147a0
  17. Oldenburg O, Cohen MV, Yellon DM, Downey JM. Mitochondrial K (ATP) channels: role in cardioprotection. Cardiovasc Res 55: 429-437, 2002 https://doi.org/10.1016/S0008-6363(02)00439-X
  18. Ordog T, Ward SM, Sanders KM. Interstitial cells of cajal generate electrical slow waves in the murine stomach. J Physiol 518: 257-269, 1999. https://doi.org/10.1111/j.1469-7793.1999.0257r.x
  19. O'Rourke B. Myocardial K (ATP) channels in preconditioning. Circ Res 87: 845-855, 2000 https://doi.org/10.1161/01.RES.87.10.845
  20. Sanders KM. A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111: 492-515, 1996 https://doi.org/10.1053/gast.1996.v111.pm8690216
  21. Seino S. ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol 61: 337-362, 1999 https://doi.org/10.1146/annurev.physiol.61.1.337
  22. Sparagna GC, Gunter KK, Sheu SS, Gunter TE. Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem 270: 27510-27515, 1995 https://doi.org/10.1074/jbc.270.46.27510
  23. Spruce AE, Standen NB, Stanfield PR. Voltage-dependent ATP-sensitive potassium channels of skeletal muscle membrane. Nature 316: 736-738, 1985 https://doi.org/10.1038/316736a0
  24. Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT. Hyperpolarizing vasodilators activate ATP sensitive $K^{+}$ channels in arterial smooth muscle. Nature 245: 177-180, 1989
  25. Szurszewski JH. Electrical basis for gastrointestinal motility. In: Johnson LR ed, Physiology of the Gastrointestinal Tract. 2nd ed. Raven Press, New York, p 383-422, 1987
  26. Thomsen L, Robinson TL, Lee JC, Farraway LA, Hughes MJ, Andrews DW, Huizinga JD. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med 4: 848-851, 1998 https://doi.org/10.1038/nm0798-848
  27. Ward SM, Burns AJ, Torihashi S, Sanders KM. Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol 480: 91-97, 1994
  28. Ward SM, Ordog T, Koh SD, Baker SA, Jun JY, Amberg G, Monaghan K, Sanders KM. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol 525: 355-361, 2000 https://doi.org/10.1111/j.1469-7793.2000.t01-1-00355.x
  29. Yao Z, Gross GJ. Effects of the KATP channel opener bimakalim on coronary blood flow monophasic action potential duration and infarct size in dogs. Circulation 89: 1769-1775, 1994 https://doi.org/10.1161/01.CIR.89.4.1769