Spontaneous Electrical Activity and Rhythmicity in Gastrointestinal Smooth Muscles

  • Kenton M. SandersEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1124)


The gastrointestinal (GI) tract has multifold tasks of ingesting, processing, and assimilating nutrients and disposing of wastes at appropriate times. These tasks are facilitated by several stereotypical motor patterns that build upon the intrinsic rhythmicity of the smooth muscles that generate phasic contractions in many regions of the gut. Phasic contractions result from a cyclical depolarization/repolarization cycle, known as electrical slow waves, which result from intrinsic pacemaker activity. Interstitial cells of Cajal (ICC) are electrically coupled to smooth muscle cells (SMCs) and generate and propagate pacemaker activity and slow waves. The mechanism of slow waves is dependent upon specialized conductances expressed by pacemaker ICC. The primary conductances responsible for slow waves in mice are Ano1, Ca2+-activated Cl channels (CaCCs), and CaV3.2, T-type, voltage-dependent Ca2+ channels. Release of Ca2+ from intracellular stores in ICC appears to be the initiator of pacemaker depolarizations, activation of T-type current provides voltage-dependent Ca2+ entry into ICC, as slow waves propagate through ICC networks, and Ca2+-induced Ca2+ release and activation of Ano1 in ICC amplifies slow wave depolarizations. Slow waves conduct to coupled SMCs, and depolarization elicited by these events enhances the open-probability of L-type voltage-dependent Ca2+ channels, promotes Ca2+ entry, and initiates contraction. Phasic contractions timed by the occurrence of slow waves provide the basis for motility patterns such as gastric peristalsis and segmentation. This chapter discusses the properties of ICC and proposed mechanism of electrical rhythmicity in GI muscles.


Interstitial cells of Cajal Pacemaker Ca2+ transient Slow wave SIP syncytium ANO1 channels T-type Ca2+ channels Electrophysiology Gastrointestinal motility 



The author is grateful for the editorial assistance of Dr. Bernard Drumm, whose careful reading of the manuscript and many suggestions improved the text and figures. I would also like to acknowledge my long-term collaborations with Profs. Sean Ward and Sang Don Koh for countless discussions, contributions, and data without which my knowledge and ability to write a chapter on GI rhythmicity would have been impossible. I would also like to acknowledge many astute contributions from Prof. David Hirst who, through yearly working trips to Reno, challenged many of the concepts we had developed from studies of cultured ICC and forced us to seek better techniques and preparations in which to investigate the mechanism of electrical slow waves in ICC. I am also extremely grateful to Nancy Horowitz, Yulia Bayguinov, Lauren O’Kane, Dr. Doug Redelman, and Byoung Koh for excellent and consistent technical support for investigations of ICC. As always, I am extremely grateful to the NIDDK for the support received through a Program Project Grant, P01 DK41315-29 and a MERIT Award, R37 DK40569.


  1. 1.
    Sanders KM, Koh SD, Ro S, Ward SM. Regulation of gastrointestinal motility-insights from smooth muscle biology. Nat Rev Gastroenterol Hepatol. 2012;9(11):633–45.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Sanders KM, Ward SM, Koh SD. Interstitial cells: regulators of smooth muscle function. Physiol Rev. 2014;94(3):859–907.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 1995;373(6512):347–9.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Langton P, Ward SM, Carl A, Norell MA, Sanders KM. Spontaneous electrical activity of interstitial cells of Cajal isolated from canine proximal colon. Proc Natl Acad Sci U S A. 1989;86(18):7280–4.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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. 1994;480. (Pt 1:91–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Cobine CA, Hannah EE, Zhu MH, Lyle HE, Rock JR, Sanders KM, et al. ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. J Physiol. 2017;595(6):2021–41.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Alvarez WCaM LJ. Action current in stomach and intestine. Am J Phys. 1922;58:476–93.CrossRefGoogle Scholar
  8. 8.
    Richter CP. Action currents from the stomach. Am J Phys. 1924;67:612–33.CrossRefGoogle Scholar
  9. 9.
    Sanders KM, Ward SM, Hennig GW. Extracellular gastrointestinal electrical recordings: movement not electrophysiology. Nat Rev Gastroenterol Hepatol. 2017;14(6):372.PubMedGoogle Scholar
  10. 10.
    Kuriyama H, Tomita T. The action potential in the smooth muscle of the guinea pig taenia coli and ureter studied by the double sucrose-gap method. J Gen Physiol. 1970;55(2):147–62.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Szurszewski JH. Mechanism of action of pentagastrin and acetylcholine on the longitudinal muscle of the canine antrum. J Physiol. 1975;252(2):335–61.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Connor JA, Prosser CL, Weems WA. A study of pace-maker activity in intestinal smooth muscle. J Physiol. 1974;240(3):671–701.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ohba M, Sakamoto Y, Tomita T. The slow wave in the circular muscle of the guinea-pig stomach. J Physiol. 1975;253(2):505–16.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bulbring E. Smooth muscle potentials recorded in the taenia coli of the guineapig. J Physiol. 1954;123(3):55P–6P.PubMedGoogle Scholar
  15. 15.
    El-Sharkaway TY, Daniel EE. Ionic mechanisms of intestinal electrical control activity. Am J Phys. 1975;229(5):1287–98.CrossRefGoogle Scholar
  16. 16.
    el-Sharkawy TY, Morgan KG, Szurszewski JH. Intracellular electrical activity of canine and human gastric smooth muscle. J Physiol. 1978;279:291–307.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Daniel EE, Honour AJ, Bogoch A. Electrical activity of the longitudinal muscle of dog small intestine studied in vivo using microelectrodes. Am J Phys. 1960;198:113–8.CrossRefGoogle Scholar
  18. 18.
    Koh SD, Ward SM, Ordog T, Sanders KM, Horowitz B. Conductances responsible for slow wave generation and propagation in interstitial cells of Cajal. Curr Opin Pharmacol. 2003;3(6):579–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Beckett EA, Bayguinov YR, Sanders KM, Ward SM, Hirst GD. Properties of unitary potentials generated by intramuscular interstitial cells of Cajal in the murine and guinea-pig gastric fundus. J Physiol. 2004;559.(Pt 1:259–69.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hirst GD, Dickens EJ, Edwards FR. Pacemaker shift in the gastric antrum of guinea-pigs produced by excitatory vagal stimulation involves intramuscular interstitial cells. J Physiol. 2002;541.(Pt 3:917–28.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hirst GD, Silverberg GD, van Helden DF. The action potential and underlying ionic currents in proximal rat middle cerebral arterioles. J Physiol. 1986;371:289–304.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kurahashi M, Zheng H, Dwyer L, Ward SM, Don Koh S, Sanders KM. A functional role for the ‘fibroblast-like cells’ in gastrointestinal smooth muscles. J Physiol. 2011;589.(Pt 3:697–710.PubMedCrossRefGoogle Scholar
  23. 23.
    Sung TS, Hwang SJ, Koh SD, Bayguinov Y, Peri LE, Blair PJ, et al. The cells and conductance mediating cholinergic neurotransmission in the murine proximal stomach. J Physiol. 2018;596:1549–74.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Code CF, Szurszewski JH. The effect of duodenal and mid small bowel transection on the frequency gradient of the pacesetter potential in the canine small intestine. J Physiol. 1970;207(2):281–9.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Thomsen L, Robinson TL, Lee JC, Farraway LA, Hughes MJ, Andrews DW, et al. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med. 1998;4(7):848–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Daniel EE, Robinson K, Duchon G, Henderson RM. The possible role of close contacts (nexuses) in the propagation of control electrical activity in the stomach and small intestine. Am J Dig Dis. 1971;16(7):611–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Christensen J, Schedl HP, Clifton JA. The small intestinal basic electrical rhythm (slow wave) frequency gradient in normal men and in patients with variety of diseases. Gastroenterology. 1966;50(3):309–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Bortoff A. Electrical transmission of slow waves from longitudinal to circular intestinal muscle. Am J Phys. 1965;209(6):1254–60.CrossRefGoogle Scholar
  29. 29.
    Bozler E. The relation of the action potentials to mechanical activity in intestinal muscle. Am J Phys. 1946;146:496–501.CrossRefGoogle Scholar
  30. 30.
    Suzuki H, Hirst GD. Regenerative potentials evoked in circular smooth muscle of the antral region of guinea-pig stomach. J Physiol. 1999;517(Pt 2):563–73.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Hirst GD, Bramich NJ, Teramoto N, Suzuki H, Edwards FR. Regenerative component of slow waves in the guinea-pig gastric antrum involves a delayed increase in [Ca(2+)](i) and Cl(−) channels. J Physiol. 2002;540.(Pt 3:907–19.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hirst GD, Edwards FR. Generation of slow waves in the antral region of guinea-pig stomach—a stochastic process. J Physiol. 2001;535.(Pt 1:165–80.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cousins HM, Edwards FR, Hickey H, Hill CE, Hirst GD. Electrical coupling between the myenteric interstitial cells of Cajal and adjacent muscle layers in the guinea-pig gastric antrum. J Physiol. 2003;550.(Pt 3:829–44.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Dickens EJ, Hirst GD, Tomita T. Identification of rhythmically active cells in guinea-pig stomach. J Physiol. 1999;514(Pt 2):515–31.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ordog T, Ward SM, Sanders KM. Interstitial cells of Cajal generate electrical slow waves in the murine stomach. J Physiol. 1999;518. (Pt 1:257–69.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Szurszewski JH. Electrical basis for gastrointestinal motility. In: Johnson LR, editor. Physiology of the gastrointestinal tract. 2nd ed. New York: Raven Press; 1981. p. 1435–66.Google Scholar
  37. 37.
    Tomita T. Electrical activity (spikes and slow waves) in gastrointestinal smooth muscles. In: Bulbring E, Brading AF, Tomita T, editors. Smooth muscle: An assessment of current knowledge. London: Edward Arnold; 1981. p. 127–56.Google Scholar
  38. 38.
    Dickens EJ, Edwards FR, Hirst GD. Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach. J Physiol. 2001;531.(Pt 3:827–33.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Horner MJ, Ward SM, Gerthoffer WT, Sanders KM, Horowitz B. Maintenance of morphology and function of canine proximal colon smooth muscle in organ culture. Am J Phys. 1997;272(3. Pt 1):G669–80.Google Scholar
  40. 40.
    Hall KA, Ward SM, Cobine CA, Keef KD. Spatial organization and coordination of slow waves in the mouse anorectum. J Physiol. 2014;592(17):3813–29.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Forster J, Damjanov I, Lin Z, Sarosiek I, Wetzel P, McCallum RW. Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointest Surg. 2005;9(1):102–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC, et al. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Neurogastroenterol Motil. 2012;24(6):531–9. e249PubMedCrossRefGoogle Scholar
  43. 43.
    Ordog T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes. 2000;49(10):1731–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Kito Y, Sanders KM, Ward SM, Suzuki H. Interstitial cells of Cajal generate spontaneous transient depolarizations in the rat gastric fundus. Am J Physiol Gastrointest Liver Physiol. 2009;297(4):G814–24.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kito Y, Suzuki H. Properties of pacemaker potentials recorded from myenteric interstitial cells of Cajal distributed in the mouse small intestine. J Physiol. 2003;553.(Pt 3:803–18.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kito Y, Ward SM, Sanders KM. Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine. Am J Phys Cell Phys. 2005;288(3):C710–20.CrossRefGoogle Scholar
  47. 47.
    Kito Y, Mitsui R, Ward SM, Sanders KM. Characterization of slow waves generated by myenteric interstitial cells of Cajal of the rabbit small intestine. Am J Physiol Gastrointest Liver Physiol. 2015;308(5):G378–88.PubMedCrossRefGoogle Scholar
  48. 48.
    Jun JY, Kong ID, Koh SD, Wang XY, Perrino BA, Ward SM, et al. Regulation of ATP-sensitive K(+) channels by protein kinase C in murine colonic myocytes. Am J Phys Cell Phys. 2001;281(3):C857–64.CrossRefGoogle Scholar
  49. 49.
    Kito Y, Kurahashi M, Mitsui R, Ward SM, Sanders KM. Spontaneous transient hyperpolarizations in the rabbit small intestine. J Physiol. 2014;592.(Pt 21:4733–45.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kelly KA, Code CF, Elveback LR. Patterns of canine gastric electrical activity. Am J Phys. 1969;217(2):461–70.CrossRefGoogle Scholar
  51. 51.
    Publicover NG, Sanders KM. A technique to locate the pacemaker in smooth muscles. J Appl Physiol. 1984;57(5):1586–90.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Bauer AJ, Reed JB, Sanders KM. Slow wave heterogeneity within the circular muscle of the canine gastric antrum. J Physiol. 1985;366:221–32.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Horiguchi K, Semple GS, Sanders KM, Ward SM. Distribution of pacemaker function through the tunica muscularis of the canine gastric antrum. J Physiol. 2001;537.(Pt 1:237–50.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Forrest AS, Ordog T, Sanders KM. Neural regulation of slow-wave frequency in the murine gastric antrum. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G486–95.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Hashitani H, Garcia-Londono AP, Hirst GD, Edwards FR. Atypical slow waves generated in gastric corpus provide dominant pacemaker activity in guinea pig stomach. J Physiol. 2005;569(Pt 2):459–65.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Rhee PL, Lee JY, Son HJ, Kim JJ, Rhee JC, Kim S, et al. Analysis of pacemaker activity in the human stomach. J Physiol. 2011;589.(Pt 24:6105–18.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hara Y, Kubota M, Szurszewski JH. Electrophysiology of smooth muscle of the small intestine of some mammals. J Physiol. 1986;372:501–20.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Jimenez M, Cayabyab FS, Vergara P, Daniel EE. Heterogeneity in electrical activity of the canine ileal circular muscle: interaction of two pacemakers. Neurogastroenterol Motil. 1996;8(4):339–49.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Durdle NG, Kingma YJ, Bowes KL, Chambers MM. Origin of slow waves in the canine colon. Gastroenterology. 1983;84(2):375–82.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Smith TK, Reed JB, Sanders KM. Interaction of two electrical pacemakers in muscularis of canine proximal colon. Am J Phys. 1987;252(3. Pt 1):C290–9.CrossRefGoogle Scholar
  61. 61.
    Smith TK, Reed JB, Sanders KM. Origin and propagation of electrical slow waves in circular muscle of canine proximal colon. Am J Phys. 1987;252(2 Pt 1):C215–24.CrossRefGoogle Scholar
  62. 62.
    Yoneda S, Takano H, Takaki M, Suzuki H. Properties of spontaneously active cells distributed in the submucosal layer of mouse proximal colon. J Physiol. 2002;542.(Pt 3:887–97.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Berezin I, Huizinga JD, Daniel EE. Interstitial cells of Cajal in the canine colon: a special communication network at the inner border of the circular muscle. J Comp Neurol. 1988;273(1):42–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Berezin I, Huizinga JD, Daniel EE. Structural characterization of interstitial cells of Cajal in myenteric plexus and muscle layers of canine colon. Can J Physiol Pharmacol. 1990;68(11):1419–31.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Suzuki N, Prosser CL, Dahms V. Boundary cells between longitudinal and circular layers: essential for electrical slow waves in cat intestine. Am J Phys. 1986;250(3 Pt 1):G287–94.Google Scholar
  66. 66.
    Ward SM, Sanders KM. Pacemaker activity in septal structures of canine colonic circular muscle. Am J Phys. 1990;259(2 Pt 1):G264–73.Google Scholar
  67. 67.
    Faussone Pellegrini MS. Ultrastructure and topography of Cajal interstitial cells in the circular muscle layer of the ileum and the colon in the rat. Boll Soc Ital Biol Sper. 1982;58(19):1260–5.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Rumessen JJ, Thuneberg L. Pacemaker cells in the gastrointestinal tract: interstitial cells of Cajal. Scand J Gastroenterol Suppl. 1996;216:82–94.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Rumessen JJ, Vanderwinden JM, Rasmussen H, Hansen A, Horn T. Ultrastructure of interstitial cells of Cajal in myenteric plexus of human colon. Cell Tissue Res. 2009;337(2):197–212.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol. 1982;71:1–130.PubMedCrossRefGoogle Scholar
  71. 71.
    Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol. 1999;62(4):295–316.PubMedCrossRefGoogle Scholar
  72. 72.
    Sanders KM, Stevens R, Burke E, Ward SW. Slow waves actively propagate at submucosal surface of circular layer in canine colon. Am J Phys. 1990;259(2 Pt 1):G258–63.Google Scholar
  73. 73.
    Carlson HC, Code CF, Nelson RA. Motor action of the canine gastroduodenal junction: a cineradiographic, pressure, and electric study. Am J Dig Dis. 1966;11(2):155–72.PubMedCrossRefGoogle Scholar
  74. 74.
    Sarna SK, Daniel EE. Electrical stimulation of gastric electrical control activity. Am J Phys. 1973;225(1):125–31.CrossRefGoogle Scholar
  75. 75.
    Bayguinov O, Hennig GW, Sanders KM. Movement based artifacts may contaminate extracellular electrical recordings from GI muscles. Neurogastroenterol Motil. 2011;23(11):1029–42. e498PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Sanders KM, Ward SM, Hennig GW. Problems with extracellular recording of electrical activity in gastrointestinal muscle. Nat Rev Gastroenterol Hepatol. 2016;13(12):731–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Bauer AJ, Publicover NG, Sanders KM. Origin and spread of slow waves in canine gastric antral circular muscle. Am J Phys. 1985;249(6 Pt 1):G800–6.Google Scholar
  78. 78.
    Ward SM, Baker SA, de Faoite A, Sanders KM. Propagation of slow waves requires IP3 receptors and mitochondrial Ca2+ uptake in canine colonic muscles. J Physiol. 2003;549(Pt 1):207–18.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ward SM, Dixon RE, de Faoite A, Sanders KM. Voltage-dependent calcium entry underlies propagation of slow waves in canine gastric antrum. J Physiol. 2004;561(Pt 3):793–810.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Bayguinov O, Ward SM, Kenyon JL, Sanders KM. Voltage-gated Ca2+ currents are necessary for slow-wave propagation in the canine gastric antrum. Am J Phys Cell Phys. 2007;293(5):C1645–59.CrossRefGoogle Scholar
  81. 81.
    Kelly KA, La Force RC. Pacing the canine stomach with electric stimulation. Am J Phys. 1972;222(3):588–94.CrossRefGoogle Scholar
  82. 82.
    Soffer EE. Gastric electrical stimulation for gastroparesis. J Neurogastroenterol Motil. 2012;18(2):131–7.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Publicover NG, Sanders KM. Effects of frequency on the wave form of propagated slow waves in canine gastric antral muscle. J Physiol. 1986;371:179–89.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Kito Y, Fukuta H, Yamamoto Y, Suzuki H. Excitation of smooth muscles isolated from the guinea-pig gastric antrum in response to depolarization. J Physiol. 2002;543(Pt 1):155–67.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Walsh JV Jr, Singer JJ. Voltage clamp of single freshly dissociated smooth muscle cells: current-voltage relationships for three currents. Pflugers Arch. 1981;390(2):207–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Yoshino M, Wang SY, Kao CY. Sodium and calcium inward currents in freshly dissociated smooth myocytes of rat uterus. J Gen Physiol. 1997;110(5):565–77.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Mitra R, Morad M. Ca2+ and Ca2+-activated K+ currents in mammalian gastric smooth muscle cells. Science. 1985;229(4710):269–72.PubMedCrossRefGoogle Scholar
  88. 88.
    Langton PD, Burke EP, Sanders KM. Participation of Ca currents in colonic electrical activity. Am J Phys. 1989;257(3 Pt 1):C451–60.CrossRefGoogle Scholar
  89. 89.
    Kuriyama H, Osa T, Toida N. Electrophysiological study of the intestinal smooth muscle of the guinea-pig. J Physiol. 1967;191(2):239–55.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Ozaki H, Stevens RJ, Blondfield DP, Publicover NG, Sanders KM. Simultaneous measurement of membrane potential, cytosolic Ca2+, and tension in intact smooth muscles. Am J Phys. 1991;260(5 Pt 1):C917–25.CrossRefGoogle Scholar
  91. 91.
    Vogalis F, Publicover NG, Hume JR, Sanders KM. Relationship between calcium current and cytosolic calcium in canine gastric smooth muscle cells. Am J Phys. 1991;260(5 Pt 1):C1012–8.CrossRefGoogle Scholar
  92. 92.
    Benham CD, Bolton TB, Denbigh JS, Lang RJ. Inward rectification in freshly isolated single smooth muscle cells of the rabbit jejunum. J Physiol. 1987;383:461–76.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Malysz J, Thuneberg L, Mikkelsen HB, Huizinga JD. Action potential generation in the small intestine of W mutant mice that lack interstitial cells of Cajal. Am J Phys. 1996;271(3 Pt 1):G387–99.Google Scholar
  94. 94.
    Ward SM, Burns AJ, Torihashi S, Harney SC, Sanders KM. Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants. Am J Phys. 1995;269(6Pt 1):C1577–85.CrossRefGoogle Scholar
  95. 95.
    Tashiro N, Tomita T. The effects of papaverine on the electrical and mechanical activity of the guinea-pig taenia coli. Br J Pharmacol. 1970;39(3):608–18.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ward SM, Dalziel HH, Khoyi MA, Westfall AS, Sanders KM, Westfall DP. Hyperpolarization and inhibition of contraction mediated by nitric oxide released from enteric inhibitory neurones in guinea-pig taenia coli. Br J Pharmacol. 1996;118(1):49–56.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Duthie HL, Kirk D. Electrical activity of human colonic smooth muscle in vitro. J Physiol. 1978;283:319–30.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Vogalis F, Ward SM, Sanders KM. Correlation between electrical and morphological properties of canine pyloric circular muscle. Am J Phys. 1991;260(3 Pt 1):G390–8.Google Scholar
  99. 99.
    Sanders KM. Excitation-contraction coupling without Ca2+ action potentials in small intestine. Am J Phys. 1983;244(5):C356–61.CrossRefGoogle Scholar
  100. 100.
    Morgan KG, Szurszewski JH. Mechanisms of phasic and tonic actions of pentagastrin on canine gastric smooth muscle. J Physiol. 1980;301:229–42.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Der-Silaphet T, Malysz J, Hagel S, Larry Arsenault A, Huizinga JD. Interstitial cells of cajal direct normal propulsive contractile activity in the mouse small intestine. Gastroenterology. 1998;114(4):724–36.PubMedCrossRefGoogle Scholar
  102. 102.
    Hennig GW, Spencer NJ, Jokela-Willis S, Bayguinov PO, Lee HT, Ritchie LA, et al. ICC-MY coordinate smooth muscle electrical and mechanical activity in the murine small intestine. Neurogastroenterol Motil. 2010;22(5):e138–51.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Yoneda S, Fukui H, Takaki M. Pacemaker activity from submucosal interstitial cells of Cajal drives high-frequency and low-amplitude circular muscle contractions in the mouse proximal colon. Neurogastroenterol Motil. 2004;16(5):621–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Rae MG, Fleming N, McGregor DB, Sanders KM, Keef KD. Control of motility patterns in the human colonic circular muscle layer by pacemaker activity. J Physiol. 1998;510(Pt 1):309–20.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Thuneberg L, Johansen V, Rumessen JJ, Anderson BG. Interstitial cells of Cajal: selective uptake of methylene blue inhibits slow wave activity. In: Roman C, editor. Gastrointestinal motility. Lancaster: Mtp Press Limited; 1984. p. 495–502.CrossRefGoogle Scholar
  106. 106.
    Torihashi S, Kobayashi S, Gerthoffer WT, Sanders KM. Interstitial cells in deep muscular plexus of canine small intestine may be specialized smooth muscle cells. Am J Phys. 1993;265(4 Pt 1):G638–45.Google Scholar
  107. 107.
    Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, et al. Requirement of c-kit for development of intestinal pacemaker system. Development. 1992;116(2):369–75.PubMedGoogle Scholar
  108. 108.
    Torihashi S, Ward SM, Nishikawa S, Nishi K, Kobayashi S, Sanders KM. c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res. 1995;280(1):97–111.PubMedGoogle Scholar
  109. 109.
    Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.PubMedCrossRefGoogle Scholar
  110. 110.
    Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, et al. Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2009;296(6):G1370–81.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Hwang SJ, Blair PJ, Britton FC, O’Driscoll KE, Hennig G, Bayguinov YR, et al. Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol. 2009;587(Pt 20):4887–904.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wouters M, De Laet A, Donck LV, Delpire E, van Bogaert PP, Timmermans JP, et al. Subtractive hybridization unravels a role for the ion cotransporter NKCC1 in the murine intestinal pacemaker. Am J Physiol Gastrointest Liver Physiol. 2006;290(6):G1219–27.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhu MH, Sung TS, Kurahashi M, O’Kane LE, O’Driscoll K, Koh SD, et al. Na+-K+-Cl− cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol. 2016;311(6):G1037–G46.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Ro S, Park C, Jin J, Zheng H, Blair PJ, Redelman D, et al. A model to study the phenotypic changes of interstitial cells of Cajal in gastrointestinal diseases. Gastroenterology. 2010;138(3):1068–78.e1–2.PubMedCrossRefGoogle Scholar
  115. 115.
    Zhu MH, Kim TW, Ro S, Yan W, Ward SM, Koh SD, et al. A Ca(2+)-activated Cl(−) conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J Physiol. 2009;587(Pt 20):4905–18.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Ordog T, Redelman D, Miller LJ, Horvath VJ, Zhong Q, Almeida-Porada G, et al. Purification of interstitial cells of Cajal by fluorescence-activated cell sorting. Am J Phys Cell Phys. 2004;286(2):C448–56.CrossRefGoogle Scholar
  117. 117.
    Lee MY, Ha SE, Park C, Park PJ, Fuchs R, Wei L, et al. Transcriptome of interstitial cells of Cajal reveals unique and selective gene signatures. PLoS One. 2017;12(4):e0176031.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Chen H, Ordog T, Chen J, Young DL, Bardsley MR, Redelman D, et al. Differential gene expression in functional classes of interstitial cells of Cajal in murine small intestine. Physiol Genomics. 2007;31(3):492–509.PubMedCrossRefGoogle Scholar
  119. 119.
    Koh SD, Sanders KM, Ward SM. Spontaneous electrical rhythmicity in cultured interstitial cells of cajal from the murine small intestine. J Physiol. 1998;513(Pt 1):203–13.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Goto K, Matsuoka S, Noma A. Two types of spontaneous depolarizations in the interstitial cells freshly prepared from the murine small intestine. J Physiol. 2004;559(Pt 2):411–22.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322(5901):590–4.CrossRefGoogle Scholar
  122. 122.
    Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134(6):1019–29.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455(7217):1210–5.CrossRefGoogle Scholar
  124. 124.
    Kashyap P, Gomez-Pinilla PJ, Pozo MJ, Cima RR, Dozois EJ, Larson DW, et al. Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation. Neurogastroenterol Motil. 2011;23(8):760–5.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN, et al. Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci U S A. 2009;106(50):21413–8.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Strege PR, Bernard CE, Mazzone A, Linden DR, Beyder A, Gibbons SJ, et al. A novel exon in the human Ca2+-activated Cl− channel Ano1 imparts greater sensitivity to intracellular Ca2. Am J Physiol Gastrointest Liver Physiol. 2015;309(9):G743–9.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Sung TS, O’Driscoll K, Zheng H, Yapp NJ, Leblanc N, Koh SD, et al. Influence of intracellular Ca2+ and alternative splicing on the pharmacological profile of ANO1 channels. Am J Phys Cell Phys. 2016;311(3):C437–51.CrossRefGoogle Scholar
  128. 128.
    Mazzone A, Bernard CE, Strege PR, Beyder A, Galietta LJ, Pasricha PJ, et al. Altered expression of Ano1 variants in human diabetic gastroparesis. J Biol Chem. 2011;286(15):13393–403.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Hwang SJ, Basma N, Sanders KM, Ward SM. Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol. 2016;173(8):1339–49.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Rock JR, Futtner CR, Harfe BD. The transmembrane protein TMEM16A is required for normal development of the murine trachea. Dev Biol. 2008;321(1):141–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Malysz J, Gibbons SJ, Saravanaperumal SA, Du P, Eisenman ST, Cao C, et al. Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2017;312(3):G228–G45.PubMedCrossRefGoogle Scholar
  132. 132.
    Heinze C, Seniuk A, Sokolov MV, Huebner AK, Klementowicz AE, Szijarto IA, et al. Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J Clin Invest. 2014;124(2):675–86.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Vooijs M, Jonkers J, Berns A. A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent. EMBO Rep. 2001;2(4):292–7.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Huizinga JD, Shin A, Chow E. Electrical coupling and pacemaker activity in colonic smooth muscle. Am J Phys. 1988;255(5 Pt 1):C653–60.CrossRefGoogle Scholar
  135. 135.
    van Helden DF, Imtiaz MS. Ca2+ phase waves: a basis for cellular pacemaking and long-range synchronicity in the guinea-pig gastric pylorus. J Physiol. 2003;548(Pt 1):271–96.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Gibbons SJ, Strege PR, Lei S, Roeder JL, Mazzone A, Ou Y, et al. The alpha1H Ca2+ channel subunit is expressed in mouse jejunal interstitial cells of Cajal and myocytes. J Cell Mol Med. 2009;13(11–12):4422–31.PubMedCrossRefGoogle Scholar
  137. 137.
    Zheng H, Park KS, Koh SD, Sanders KM. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Phys Cell Phys. 2014;306(7):C705–13.CrossRefGoogle Scholar
  138. 138.
    Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev. 2005;57(4):411–25.PubMedCrossRefGoogle Scholar
  139. 139.
    Iftinca M, McKay BE, Snutch TP, McRory JE, Turner RW, Zamponi GW. Temperature dependence of T-type calcium channel gating. Neuroscience. 2006;142(4):1031–42.PubMedCrossRefGoogle Scholar
  140. 140.
    Kito Y, Suzuki H. Effects of temperature on pacemaker potentials in the mouse small intestine. Pflugers Arch. 2007;454(2):263–75.PubMedCrossRefGoogle Scholar
  141. 141.
    Huang X, Lee SH, Lu H, Sanders KM, Koh SD. Molecular and functional characterization of inwardly rectifying K(+) currents in murine proximal colon. J Physiol. 2018;596(3):379–91.PubMedCrossRefGoogle Scholar
  142. 142.
    Na JS, Hong C, Kim MW, Park CG, Kang HG, Wu MJ, et al. ATP-sensitive K(+) channels maintain resting membrane potential in interstitial cells of Cajal from the mouse colon. Eur J Pharmacol. 2017;809:98–104.PubMedCrossRefGoogle Scholar
  143. 143.
    Markadieu N, Delpire E. Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Arch. 2014;466(1):91–105.PubMedCrossRefGoogle Scholar
  144. 144.
    Ebihara S, Shirato K, Harata N, Akaike N. Gramicidin-perforated patch recording: GABA response in mammalian neurones with intact intracellular chloride. J Physiol. 1995;484(Pt 1):77–86.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Ball ER, Matsuda MM, Dye L, Hoffmann V, Zerfas PM, Szarek E, et al. Ultra-structural identification of interstitial cells of Cajal in the zebrafish Danio rerio. Cell Tissue Res. 2012;349(2):483–91.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Rich A, Gordon S, Brown C, Gibbons SJ, Schaefer K, Hennig G, et al. Kit signaling is required for development of coordinated motility patterns in zebrafish gastrointestinal tract. Zebrafish. 2013;10:154–60.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Brijs J, Hennig GW, Kellermann AM, Axelsson M, Olsson C. The presence and role of interstitial cells of Cajal in the proximal intestine of shorthorn sculpin (Myoxocephalus scorpius). J Exp Biol. 2017;220(Pt 3):347–57.PubMedCrossRefGoogle Scholar
  148. 148.
    Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, et al. Ano1, a Ca2+-activated Cl− channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal. J Physiol. 2014;592(Pt 18):4051–68.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Hennig GW, Hirst GD, Park KJ, Smith CB, Sanders KM, Ward SM, et al. Propagation of pacemaker activity in the guinea-pig antrum. J Physiol. 2004;556(Pt 2):585–99.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Lee HT, Hennig GW, Fleming NW, Keef KD, Spencer NJ, Ward SM, et al. The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine. Gastroenterology. 2007;132(5):1852–65.PubMedCrossRefGoogle Scholar
  151. 151.
    Lee HT, Hennig GW, Fleming NW, Keef KD, Spencer NJ, Ward SM, et al. Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum. Gastroenterology. 2007;133(3):907–17.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Lee HT, Hennig GW, Park KJ, Bayguinov PO, Ward SM, Sanders KM, et al. Heterogeneities in ICC Ca2+ activity within canine large intestine. Gastroenterology. 2009;136(7):2226–36.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Park KJ, Hennig GW, Lee HT, Spencer NJ, Ward SM, Smith TK, et al. Spatial and temporal mapping of pacemaker activity in interstitial cells of Cajal in mouse ileum in situ. Am J Phys Cell Phys. 2006;290(5):C1411–27.CrossRefGoogle Scholar
  154. 154.
    Huizinga JD, Chen JH, Zhu YF, Pawelka A, McGinn RJ, Bardakjian BL, et al. The origin of segmentation motor activity in the intestine. Nat Commun. 2014;5:3326.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Yamazawa T, Iino M. Simultaneous imaging of Ca2+ signals in interstitial cells of Cajal and longitudinal smooth muscle cells during rhythmic activity in mouse ileum. J Physiol. 2002;538(Pt 3):823–35.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Baker SA, Drumm BT, Saur D, Hennig GW, Ward SM, Sanders KM. Spontaneous Ca(2+) transients in interstitial cells of Cajal located within the deep muscular plexus of the murine small intestine. J Physiol. 2016;594(12):3317–38.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Drumm BT, Hennig GW, Battersby MJ, Cunningham EK, Sung TS, Ward SM, et al. Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. J Gen Physiol. 2017;149(7):703–25.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Lowie BJ, Wang XY, White EJ, Huizinga JD. On the origin of rhythmic calcium transients in the ICC-MP of the mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G835–45.PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Serio R, Barajas-Lopez C, Daniel EE, Berezin I, Huizinga JD. Slow-wave activity in colon: role of network of submucosal interstitial cells of Cajal. Am J Phys. 1991;260(4 Pt 1):G636–45.Google Scholar
  160. 160.
    Bayguinov PO, Hennig GW, Smith TK. Ca2+ imaging of activity in ICC-MY during local mucosal reflexes and the colonic migrating motor complex in the murine large intestine. J Physiol. 2010;588(Pt 22):4453–74.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Huang L, Keyser BM, Tagmose TM, Hansen JB, Taylor JT, Zhuang H, et al. NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: a new selective inhibitor of T-type calcium channels. J Pharmacol Exp Ther. 2004;309(1):193–9.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Kraus RL, Li Y, Gregan Y, Gotter AL, Uebele VN, Fox SV, et al. In vitro characterization of T-type calcium channel antagonist TTA-A2 and in vivo effects on arousal in mice. J Pharmacol Exp Ther. 2010;335(2):409–17.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Suzuki H, Takano H, Yamamoto Y, Komuro T, Saito M, Kato K, et al. Properties of gastric smooth muscles obtained from mice which lack inositol trisphosphate receptor. J Physiol. 2000;525(Pt 1):105–11.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P, Dosen PJ. Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric pylorus. J Physiol. 2000;524(Pt 1):245–65.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Ganitkevich V, Isenberg G. Membrane potential modulates inositol 1,4,5-trisphosphate-mediated Ca2+ transients in guinea-pig coronary myocytes. J Physiol. 1993;470:35–44.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Fukuta H, Kito Y, Suzuki H. Spontaneous electrical activity and associated changes in calcium concentration in guinea-pig gastric smooth muscle. J Physiol. 2002;540(Pt 1):249–60.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Malysz J, Donnelly G, Huizinga JD. Regulation of slow wave frequency by IP(3)-sensitive calcium release in the murine small intestine. Am J Physiol Gastrointest Liver Physiol. 2001;280(3):G439–48.PubMedCrossRefGoogle Scholar
  168. 168.
    Ward SM, Ordog T, Koh SD, Baker SA, Jun JY, Amberg G, et al. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol. 2000;525(Pt 2):355–61.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Liu HN, Ohya S, Wang J, Imaizumi Y, Nakayama S. Involvement of ryanodine receptors in pacemaker Ca2+ oscillation in murine gastric ICC. Biochem Biophys Res Commun. 2005;328(2):640–6.PubMedCrossRefGoogle Scholar
  170. 170.
    Zhu MH, Sung TS, O’Driscoll K, Koh SD, Sanders KM. Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal. Am J Phys Cell Phys. 2015;308(8):C608–20.CrossRefGoogle Scholar
  171. 171.
    Faussone-Pellegrini MS. Cytodifferentiation of the interstitial cells of Cajal related to the myenteric plexus of mouse intestinal muscle coat. An E.M. study from foetal to adult life. Anat Embryol. 1985;171(2):163–9.PubMedCrossRefGoogle Scholar
  172. 172.
    Rumessen JJ, Thuneberg L. Interstitial cells of Cajal in human small intestine. Ultrastructural identification and organization between the main smooth muscle layers. Gastroenterology. 1991;100(5 Pt 1):1417–31.PubMedCrossRefGoogle Scholar
  173. 173.
    Kito Y, Suzuki H. Electrophysiological properties of gastric pacemaker potentials. J Smooth Muscle Res. 2003;39(5):163–73.PubMedCrossRefGoogle Scholar
  174. 174.
    Kito Y, Fukuta H, Suzuki H. Components of pacemaker potentials recorded from the guinea pig stomach antrum. Pflugers Arch. 2002;445(2):202–17.PubMedCrossRefGoogle Scholar
  175. 175.
    Faville RA, Pullan AJ, Sanders KM, Koh SD, Lloyd CM, Smith NP. Biophysically based mathematical modeling of interstitial cells of Cajal slow wave activity generated from a discrete unitary potential basis. Biophys J. 2009;96(12):4834–52.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Drumm BT, Sung TS, Zheng H, Baker SA, Koh SD, Sanders KM. The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine. Cell Calcium. 2018;72(June):1–17.PubMedCrossRefGoogle Scholar
  177. 177.
    Kito Y, Suzuki H. Modulation of slow waves by hyperpolarization with potassium channel openers in antral smooth muscle of the guinea-pig stomach. J Physiol. 2003;548(Pt 1):175–89.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Lee JY, Ko EJ, Ahn KD, Kim S, Rhee PL. The role of K(+) conductances in regulating membrane excitability in human gastric corpus smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2015;308(7):G625–33.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Koh SD, Bradley KK, Rae MG, Keef KD, Horowitz B, Sanders KM. Basal activation of ATP-sensitive potassium channels in murine colonic smooth muscle cell. Biophys J. 1998;75(4):1793–800.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Kurahashi M, Mutafova-Yambolieva V, Koh SD, Sanders KM. Platelet-derived growth factor receptor-alpha-positive cells and not smooth muscle cells mediate purinergic hyperpolarization in murine colonic muscles. Am J Phys Cell Phys. 2014;307(6):C561–70.CrossRefGoogle Scholar
  181. 181.
    Chow E, Huizinga JD. Myogenic electrical control activity in longitudinal muscle of human and dog colon. J Physiol. 1987;392:21–34.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Burns AJ, Lomax AE, Torihashi S, Sanders KM, Ward SM. Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A. 1996;93(21):12008–13.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Ward SM, Beckett EA, Wang X, Baker F, Khoyi M, Sanders KM. Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci. 2000;20(4):1393–403.PubMedCrossRefGoogle Scholar
  184. 184.
    Goyal RK. CrossTalk opposing view: interstitial cells are not involved and physiologically important in neuromuscular transmission in the gut. J Physiol. 2016;594(6):1511–3.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Goyal RK, Chaudhury A. Mounting evidence against the role of ICC in neurotransmission to smooth muscle in the gut. Am J Physiol Gastrointest Liver Physiol. 2010;298(1):G10–3.PubMedCrossRefGoogle Scholar
  186. 186.
    Sanders KM, Hwang SJ, Ward SM. Neuroeffector apparatus in gastrointestinal smooth muscle organs. J Physiol. 2010;588(Pt 23):4621–39.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Sanders KM, Ward SM, Friebe A. CrossTalk proposal: interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol. 2016;594(6):1507–9.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Rumessen JJ, Mikkelsen HB, Thuneberg L. Ultrastructure of interstitial cells of Cajal associated with deep muscular plexus of human small intestine. Gastroenterology. 1992;102(1):56–68.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Zhou DS, Komuro T. Ultrastructure of the zinc iodide-osmic acid stained cells in guinea pig small intestine. J Anat. 1995;187(Pt 2):481–5.PubMedPubMedCentralGoogle Scholar
  190. 190.
    Sternini C, Su D, Gamp PD, Bunnett NW. Cellular sites of expression of the neurokinin-1 receptor in the rat gastrointestinal tract. J Comp Neurol. 1995;358(4):531–40.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Vannucchi MG, De Giorgio R, Faussone-Pellegrini MS. NK1 receptor expression in the interstitial cells of Cajal and neurons and tachykinins distribution in rat ileum during development. J Comp Neurol. 1997;383(2):153–62.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Iino S, Ward SM, Sanders KM. Interstitial cells of Cajal are functionally innervated by excitatory motor neurones in the murine intestine. J Physiol. 2004;556(Pt 2):521–30.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Wang XY, Ward SM, Gerthoffer WT, Sanders KM. PKC-epsilon translocation in enteric neurons and interstitial cells of Cajal in response to muscarinic stimulation. Am J Physiol Gastrointest Liver Physiol. 2003;285(3):G593–601.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Baker SA, Drumm BT, Skowronek KE, Rembetski BE, Peri LE, Hennig GW, Perrino BA, Sanders KM. Excitatory neuronal responses of Ca(2+) transients in interstitial cells of Cajal in the small intestine. eNeuro. 2018;5(2). pii: ENEURO.0080-18.2018.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Baker SA, Drumm BT, et al. Inhibitory neural regulation of the Ca2+ transients in intramuscular interstitial cells of Cajal in the small intestine. Front Physiol. 2018;9:328.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Inoue R, Isenberg G. Effect of membrane potential on acetylcholine-induced inward current in guinea-pig ileum. J Physiol. 1990;424:57–71.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Gordienko DV, Zholos AV. Regulation of muscarinic cationic current in myocytes from guinea-pig ileum by intracellular Ca2+ release: a central role of inositol 1,4,5-trisphosphate receptors. Cell Calcium. 2004;36(5):367–86.PubMedCrossRefGoogle Scholar
  198. 198.
    Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, et al. Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology. 2009;137(4):1415–24.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Bhetwal BP, Sanders KM, An C, Trappanese DM, Moreland RS, Perrino BA. Ca2+ sensitization pathways accessed by cholinergic neurotransmission in the murine gastric fundus. J Physiol. 2013;591(Pt 12):2971–86.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Diamant NE, Bortoff A. Nature of the intestinal slow-wave frequency gradient. Am J Phys. 1969;216(2):301–7.CrossRefGoogle Scholar
  201. 201.
    Suzuki N, Prosser CL, DeVos W. Waxing and waning of slow waves in intestinal musculature. Am J Phys. 1986;250(1 Pt 1):G28–34.Google Scholar
  202. 202.
    Zhu MH, Sung IK, Zheng H, Sung TS, Britton FC, O’Driscoll K, et al. Muscarinic activation of Ca2+-activated Cl− current in interstitial cells of Cajal. J Physiol. 2011;589(Pt 18):4565–82.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Won KJ, Sanders KM, Ward SM. Interstitial cells of Cajal mediate mechanosensitive responses in the stomach. Proc Natl Acad Sci U S A. 2005;102(41):14913–8.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Kaji N, Horiguchi K, Iino S, Nakayama S, Ohwada T, Otani Y, et al. Nitric oxide-induced oxidative stress impairs pacemaker function of murine interstitial cells of Cajal during inflammation. Pharmacol Res. 2016;111:838–48.PubMedCrossRefGoogle Scholar
  205. 205.
    Joddar B, Tasnim N, Thakur V, Kumar A, McCallum RW, Chattopadhyay M. Delivery of mesenchymal stem cells from gelatin-alginate hydrogels to stomach lumen for treatment of gastroparesis. Bioengineering (Basel). 2018;5(1):E12.CrossRefGoogle Scholar
  206. 206.
    Sanders KM, Kito Y, Hwang SJ, Ward SM. Regulation of gastrointestinal smooth muscle function by interstitial cells. Physiology (Bethesda). 2016;31(5):316–26.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Physiology and Cell BiologyUniversity of Nevada, Reno School of MedicineRenoUSA

Personalised recommendations