Mechanisms of electrical activation and conduction in the gastrointestinal system: Lessons from cardiac electrophysiology

Frontiers in Physiology

Volumn 7, Issue MAY, 2016, Pages

  Tse, Gary ^a   Lai, Eric Tsz Him ^a   Yeo, Jie Ming ^b   Tse, Vivian ^c   Wong, Sunny Hei ^d  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b IMPERIAL COLLEGE LONDON   (United Kingdom)

^c MCGILL UNIVERSITY   (Canada)

^d CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

Cardiac electrophysiology; Conduction; Electrical excitation; Gastrointestinal electrophysiology; Propagation

Indexed keywords

CHLORIDE CHANNEL; CROFELEMER; DOMPERIDONE; LUBIPROSTONE; MACROLIDE; METOCLOPRAMIDE;

CHANNELOPATHY; CONSTIPATION; DIARRHEA; ELECTRIC CONDUCTIVITY; ELECTROSTIMULATION; ESOPHAGUS ACHALASIA; EVOKED RESPONSE; EXCITATION CONTRACTION COUPLING; GAP JUNCTION; GASTROESOPHAGEAL REFLUX; GASTROINTESTINAL MOTILITY DISORDER; GASTROINTESTINAL TRACT; HEART ARRHYTHMIA; HEART ELECTROPHYSIOLOGY; HEART MUSCLE POTENTIAL; HUMAN; INFLAMMATORY BOWEL DISEASE; IRRITABLE COLON; NONHUMAN; PACEMAKER IMPLANTATION; REVIEW; SIGNAL PROCESSING; SINUS NODE; STOMACH PARESIS;

EID: 84974556133     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2016.00182     Document Type: Review

References (200)

1. Abell, T. L., Familoni, B., Voeller, G., Werkman, R., Dean, P., Waters, B., et al. (2009). Electrophysiologic, morphologic, and serologic features of chronic unexplained nausea and vomiting: lessons learned from 121 consecutive patients. Surgery 145, 476-485. doi: 10.1016/j.surg.2008.12.006
2. Abrahamsson, H. (2007). Treatment options for patients with severe gastroparesis. Gut 56, 877-883. doi: 10.1136/gut.2005.078121
3. Akbarali, H. I. G., Hawkins, E., Ross, G. R., and Kang, M. (2010). Ion channel remodeling in gastrointestinal inflammation. Neurogastroenterol. Motil. 22, 1045-1055. doi: 10.1111/j.1365-2982.2010.01560.x
4. Aliev, R. R., Richards, W., and Wikswo, J. P. (2000). A simple nonlinear model of electrical activity in the intestine. J. Theor. Biol. 204, 21-28. doi: 10.1006/jtbi.2000.1069
5. Allessie, M. A., Bonke, F. I., and Schopman, F. J. (1976). Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes. Circ. Res. 39, 168-177. doi: 10.1161/01.RES.39.2.168
6. Allessie, M. A., Schalij, M. J., Kirchhof, C. J., Boersma, L., Huybers, M., and Hollen, J. (1989). Experimental electrophysiology and arrhythmogenicity. Anisotropy and ventricular tachycardia. Eur. Heart J. 10, 2-8. doi: 10.1093/eurheartj/10.suppl_E.2
7. Andresen, V., Camilleri, M., Busciglio, I. A., Grudell, A., Burton, D., McKinzie, S., et al. (2007). Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 133, 761-768. doi: 10.1053/j.gastro.2007.06.067
8. Angeli, T. R., O'Grady, G., Du, P., Paskaranandavadivel, N., Pullan, A. J., Bissett, I. P., et al. (2013). Circumferential and functional re-entry of in vivo slow-wave activity in the porcine small intestine. Neurogastroenterol. Motil. 25, e304-e314. doi: 10.1111/nmo.12085
9. Aonuma, K., Rozanski, J. J., Barold, S. S., DeWitt, P. L., Gosselin, A. J., and Lister, J. W. (1985). Externally activated antitachycardia pacemaker with noninvasive electrophysiologic re-testing capability. Pacing Clin. Electrophysiol. 8, 215-224. doi: 10.1111/j.1540-8159.1985.tb05752.x
10. Bardakjian, B. L., and Diamant, N. E. (1994). A mapped clock oscillator model for transmembrane electrical rhythmic activity in excitable cells. J. Theor. Biol. 166, 225-235. doi: 10.1006/jtbi.1994.1020
11. Barr, L., Dewey, M. M., and Berger, W. (1965). Propagation of action potentials and the structure of the nexus in cardiac muscle. J. Gen. Physiol. 48, 797-823. doi: 10.1085/jgp.48.5.797
12. Baruscotti, M., Bucchi, A., and Difrancesco, D. (2005). Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol. Ther. 107, 59-79. doi: 10.1016/j.pharmthera.2005.01.005
13. Beckett, E. A., McGeough, C. A., Sanders, K. M., and Ward, S. M. (2003). Pacing of interstitial cells of Cajal in the murine gastric antrum: neurally mediated and direct stimulation. J. Physiol. 553, 545-559. doi: 10.1113/jphysiol.2003.050419
14. Beckett, E. A., Takeda, Y., Yanase, H., Sanders, K. M., and Ward, S. M. (2005). Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach. J. Comp. Neurol. 493, 193-206. doi: 10.1002/cne.20746
15. Beyak, M. J., and Vanner, S. (2005). Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol. Motil. 17, 175-186. doi: 10.1111/j.1365-2982.2004.00596.x
16. Bharucha, A. E., Manduca, A., Lake, D. S., Fidler, J., Edwards, P., Grimm, R. C., et al. (2011). Gastric motor disturbances in patients with idiopathic rapid gastric emptying. Neurogastroenterol. Motil. 23, 617-e252. doi: 10.1111/j.1365-2982.2011.01710.x
17. Bradshaw, L. A., Cheng, L. K., Chung, E., Obioha, C. B., Erickson, J. C., Gorman, B. L., et al. (2016). Diabetic gastroparesis alters the biomagnetic signature of the gastric slow wave. Neurogastroenterol. Motil. 28, 837-848. doi: 10.1111/nmo.12780
18. Brugada, P., and Brugada, J. (1992). Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 20, 1391-1396. doi: 10.1016/0735-1097(92)90253-J
19. Bülbring, E. (1955). Correlation between membrane potential, spike discharge and tension in smooth muscle. J. Physiol. 128, 200-221. doi: 10.1113/jphysiol.1955.sp005299
20. Camilleri, M. (2011). New treatment options for chronic constipation: mechanisms, efficacy and safety. Can. J. Gastroenterol. 25, 29B-35B. doi: 10.1155/2011/527583
21. Camilleri, M., Bharucha, A. E., Ueno, R., Burton, D., Thomforde, G. M., Baxter, K., et al. (2006). Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G942-G947. doi: 10.1152/ajpgi.00264.2005
22. Chan, R., Wong, V. W., Chu, W. C., Wong, G. L., Li, L. S., Leung, J., et al. (2015). Diet-quality scores and prevalence of nonalcoholic fatty Liver Disease: a population study using proton-magnetic resonance spectroscopy. PLoS ONE 10:e0139310. doi: 10.1371/journal.pone.0139310
23. Chang, J. Y., and Talley, N. J. (2010). Current and emerging therapies in irritable bowel syndrome: from pathophysiology to treatment. Trends Pharmacol. Sci. 31, 326-334. doi: 10.1016/j.tips.2010.04.008
24. Chen, J. H., Wang, X. Y., Liu, L. W., Yu, W., Yu, Y., Zhao, L., et al. (2013). On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study. Front. Neurosci. 7:77. doi: 10.3389/fnins.2013.00077
25. Chen, S., Liu, L., Guo, X., Yao, S., Li, Y., Chen, S., et al. (2016). Effects of colonic electrical stimulation using different individual parameter patterns and stimulation sites on gastrointestinal transit time, defecation, and food intake. Int. J. Colorectal Dis. 31, 429-437. doi: 10.1007/s00384-015-2457-6
26. Chen, Z., Sun, B., Tse, G., Jiang, J., and Xu, W. (2016). Reversibility of both sinus node dysfunction and reduced HCN4 mRNA expression level in an atrial tachycardia pacing model of tachycardia-bradycardia syndrome in rabbit hearts. Int. J. Clin. Exp. Pathol. 9.
27. Cheng, L. K. (2015). Slow wave conduction patterns in the stomach: from waller's foundations to current challenges. Acta Physiol. 213, 384-393. doi: 10.1111/apha.12406
28. Cheung, C. K., Lee, Y. Y., Chan, Y., Cheong, P. K., Law, W. T., Lee, S. F., et al. (2013). Decreased Basal and postprandial plasma serotonin levels in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 11, 1125-1129. doi: 10.1016/j.cgh.2013.03.026
29. Cheung, C. K., and Wu, J. C. (2013). Role of ghrelin in the pathophysiology of gastrointestinal disease. Gut Liver 7, 505-512. doi: 10.5009/gnl.2013.7.5.505
30. Cho, W. J., and Daniel, E. E. (2005). Proteins of interstitial cells of Cajal and intestinal smooth muscle, colocalized with caveolin-1. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G571-G585. doi: 10.1152/ajpgi.00222.2004
31. Choy, L., Yeo, J. M., Tse, V., Chan, S. P., and Tse, G. (2016). Cardiac disease and arrhythmogenesis: mechanistic insights from mouse models. Int. J. Cardiol. Heart Vasc. 12, 1-10. doi: 10.1016/j.ijcha.2016.05.005
32. Christensen, J., Schedl, H. P., and Clifton, J. A. (1966). The small intestinal basic electrical rhythm (slow wave) frequency gradient in normal men and in patients with variety of diseases. Gastroenterology 50, 309-315.
33. Cousins, H. M., Edwards, F. R., Hickey, H., Hill, C. E., and Hirst, G. D. (2003). Electrical coupling between the myenteric interstitial cells of Cajal and adjacent muscle layers in the guinea-pig gastric antrum. J. Physiol. 550, 829-844. doi: 10.1113/jphysiol.2003.042176
34. Daniel, E. E. (2004). Communication between interstitial cells of Cajal and gastrointestinal muscle. Neurogastroenterol. Motil. 16, 118-122. doi: 10.1111/j.1743-3150.2004.00486.x
35. Daniel, E. E., Bardakjian, B. L., Huizinga, J. D., and Diamant, N. E. (1994). Relaxation oscillator and core conductor models are needed for understanding of GI electrical activities. Am. J. Physiol. 266, G339-G349.
36. Daniel, E. E., and Wang, Y. F. (1999). Gap junctions in intestinal smooth muscle and interstitial cells of Cajal. Microsc. Res. Tech. 47, 309-320.
37. Daniel, E. E., Wang, Y. F., and Cayabyab, F. S. (1998). Role of gap junctions in structural arrangements of interstitial cells of Cajal and canine ileal smooth muscle. Am. J. Physiol. 274, G1125-G1141.
38. Daniel, E. E., Yazbi, A. E., Mannarino, M., Galante, G., Boddy, G., Livergant, J., et al. (2007). Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine? Am. J. Physiol. Gastrointest. Liver Physiol. 292, G734-G745. doi: 10.1152/ajpgi.00428.2006
39. Dellon, E. S., and Ringel, Y. (2006). Treatment of functional diarrhea. Curr. Treat. Options Gastroenterol. 9, 331-342. doi: 10.1007/s11938-006-0015-6
40. Der, T., Bercik, P., Donnelly, G., Jackson, T., Berezin, I., Collins, S. M., et al. (2000). Interstitial cells of cajal and inflammation-induced motor dysfunction in the mouse small intestine. Gastroenterology 119, 1590-1599. doi: 10.1053/gast.2000.20221
41. Dewey, M. M., and Barr, L. (1962). Intercellular connection between smooth muscle cells: the nexus. Science 137, 670-672. doi: 10.1126/science.137.3531.670-a
42. Diamant, N. E., and Bortoff, A. (1969). Nature of the intestinal slow-wave frequency gradient. Am. J. Physiol. 216, 301-307.
43. Dickens, E. J., Edwards, F. R., and Hirst, G. D. (2001). Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach. J. Physiol. 531, 827-833. doi: 10.1111/j.1469-7793.2001.0827h.x
44. Dickens, E. J., Hirst, G. D., and Tomita, T. (1999). Identification of rhythmically active cells in guinea-pig stomach. J. Physiol. 514, 515-531. doi: 10.1111/j.1469-7793.1999.515ae.x
45. DiFrancesco, D. (1993). Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55, 455-472. doi: 10.1146/annurev.ph.55.030193.002323
46. Eshraghian, A., and Eshraghian, H. (2011). Interstitial cells of Cajal: a novel hypothesis for the pathophysiology of irritable bowel syndrome. Can. J. Gastroenterol. 25, 277-279. doi: 10.1155/2011/478370
47. Ey, B., Eyking, A., Gerken, G., Podolsky, D. K., and Cario, E. (2009). TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury. J. Biol. Chem. 284, 22332-22343. doi: 10.1074/jbc.M901619200
48. Farrugia, G., Lei, S., Lin, X., Miller, S. M., Nath, K. A., Ferris, C. D., et al. (2003). A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract. Proc. Natl. Acad. Sci. U.S.A. 100, 8567-8570. doi: 10.1073/pnas.1431233100
49. Faussone-Pellegrini, M. S., and Cortesini, C. (1985a). The muscle coat of the lower esophageal sphincter in patients with achalasia and hypertensive sphincter. An electron microscopic study. J. Submicrosc. Cytol. 17, 673-685.
50. Faussone-Pellegrini, M. S., and Cortesini, C. (1985b). Ultrastructural features and localization of the interstitial cells of Cajal in the smooth muscle coat of human esophagus. J. Submicrosc. Cytol. 17, 187-197.
51. Feldstein, A. E., Miller, S. M., El-Youssef, M., Rodeberg, D., Lindor, N. M., Burgart, L. J., et al. (2003). Chronic intestinal pseudoobstruction associated with altered interstitial cells of cajal networks. J. Pediatr. Gastroenterol. Nutr. 36, 492-497. doi: 10.1097/00005176-200304000-00016
52. Fujita, A., Takeuchi, T., Saitoh, N., Hanai, J., and Hata, F. (2001). Expression of Ca(2+)-activated K(+) channels, SK3, in the interstitial cells of Cajal in the gastrointestinal tract. Am. J. Physiol. Cell Physiol. 281, C1727-C1733.
53. Fukushi, Y., Sakurai, T., and Terakawa, S. (2014). Cell-to-cell propagation of intracellular signals fluorescently visualized with acridine orange in the gastric glands of guinea pigs. Biochem. Biophys. Res. Commun. 447, 38-43. doi: 10.1016/j.bbrc.2014.03.095
54. Gao, J., Du, P., O'Grady, G., Archer, R., Farrugia, G., Gibbons, S. J., et al. (2013). Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties. J. R. Soc. Interface 10:20130421. doi: 10.1098/rsif.2013.0421
55. George, S. A., Sciuto, K. J., Lin, J., Salama, M. E., Keener, J. P., Gourdie, R. G., et al. (2015). Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene. Pflugers Arch. 467, 2287-2297. doi: 10.1007/s00424-015-1698-0
56. Goldblum, J. R., Whyte, R. I., Orringer, M. B., and Appelman, H. D. (1994). Achalasia. A morphologic study of 42 resected specimens. Am. J. Surg. Pathol. 18, 327-337. doi: 10.1097/00000478-199404000-00001
57. Gomez-Pinilla, P. J., Gibbons, S. J., Bardsley, M. R., Lorincz, A., Pozo, M. J., Pasricha, P. J., et al. (2009). Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1370-G1381. doi: 10.1152/ajpgi.00074.2009
58. Hall, K. E., El-Sharkawy, T. Y., and Diamant, N. E. (1982). Vagal control of migrating motor complex in the dog. Am. J. Physiol. Gastrointest. Liver Physiol. 243, G276-G284.
59. Hanani, M., Farrugia, G., and Komuro, T. (2005). Intercellular coupling of interstitial cells of cajal in the digestive tract. Int. Rev. Cytol. 242, 249-282. doi: 10.1016/S0074-7696(04)42006-3
60. Harris, A. L. (2001). Emerging issues of connexin channels: biophysics fills the gap. Q. Rev. Biophys. 34, 325-472. doi: 10.1017/S0033583501003705
61. Hatton, W. J., Mason, H. S., Carl, A., Doherty, P., Latten, M. J., Kenyon, J. L., et al. (2001). Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal. J. Physiol. 533, 315-327. doi: 10.1111/j.1469-7793.2001.0315a.x
62. Hicks, G. A. (2006). TRP channels as therapeutic targets: hot property, or time to cool down? Neurogastroenterol. Motil. 18, 590-594. doi: 10.1111/j.1365-2982.2006.00823.x
63. Homma, S., Satoh, K., Matsuo, H., Yagi, M., Hasegawa, J., Maruta, T., et al. (2004). Electrogastrographic activity in patients who received proximal gastrectomy plus jejunal interposition or total gastrectomy plus jejunal interposition. J. Smooth Muscle Res. 40, 271-280. doi: 10.1540/jsmr.40.271
64. Hsieh, Y. C., Lin, J. C., Hung, C. Y., Li, C. H., Lin, S. F., Yeh, H. I., et al. (2015). Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts. Heart Rhythm 13, 251-261. doi: 10.1016/j.hrthm.2015.07.023
65. Hsieh, Y. C., Lin, S. F., Lin, T. C., Ting, C. T., and Wu, T. J. (2009). Therapeutic hypothermia (30 degrees C) enhances arrhythmogenic substrates, including spatially discordant alternans, and facilitates pacing-induced ventricular fibrillation in isolated rabbit hearts. Circ. J. 73, 2214-2222. doi: 10.1253/circj.CJ-09-0432
66. Huizinga, J. D., Golden, C. M., Zhu, Y., and White, E. J. (2004). Ion channels in interstitial cells of Cajal as targets for neurotransmitter action. Neurogastroenterol. Motil. 16 (Suppl. 1), 106-111. doi: 10.1111/j.1743-3150.2004.00484.x
67. Huizinga, J. D., Thuneberg, L., Klüppel, 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. doi: 10.1038/373347a0
68. Iino, S., Asamoto, K., and Nojyo, Y. (2001). Heterogeneous distribution of a gap junction protein, connexin43, in the gastroduodenal junction of the guinea pig. Auton. Neurosci. 93, 8-13. doi: 10.1016/S1566-0702(01)00320-4
69. Irimia, A., and Wikswo, J. P. Jr. (2008). Gastrointestinal arrhythmias are associated with statistically significant fluctuations in systemic information dimension. Physiol. Meas. 29, N33-N40. doi: 10.1088/0967-3334/29/5/N01
70. Ito, Y., Shiga, K., Yoshida, K., Ogata, K., Kandori, A., Inaba, T., et al. (2014). Development of a magnetocardiography-based algorithm for discrimination between ventricular arrhythmias originating from the right ventricular outflow tract and those originating from the aortic sinus cusp: a pilot study. Heart Rhythm 11, 1605-1612. doi: 10.1016/j.hrthm.2014.05.032
71. Jin, N. G., Koh, S. D., and Sanders, K. M. (2009). Caffeine inhibits nonselective cationic currents in interstitial cells of Cajal from the murine jejunum. Am. J. Physiol. Cell Physiol. 297, C971-C978. doi: 10.1152/ajpcell.00155.2009
72. 2+ influx and expression of TRPC genes in mouse sinoatrial node. Circ. Res. 100, 1605-1614. doi: 10.1161/CIRCRESAHA.107.152181
73. Jung, K. T., Park, H., Kim, J. H., Shin, D. J., Joung, B. Y., Lee, M. H., et al. (2012). The relationship between gastric myoelectric activity and SCN5A mutation suggesting sodium channelopathy in patients with brugada syndrome and functional dyspepsia-a pilot study. J. Neurogastroenterol. Motil. 18, 58-63. doi: 10.5056/jnm.2012.18.1.58
74. Kelly, K. A., and Code, C. F. (1971). Canine gastric pacemaker. Am. J. Physiol. Legacy Content 220, 112-118.
75. Kenny, S. E., Connell, M. G., Rintala, R. J., Vaillant, C., Edgar, D. H., and Lloyd, D. A. (1998). Abnormal colonic interstitial cells of Cajal in children with anorectal malformations. J. Pediatr. Surg. 33, 130-132. doi: 10.1016/S0022-3468(98)90379-7
76. Khelif, K., De Laet, M. H., Chaouachi, B., Segers, V., and Vanderwinden, J. M. (2003). Achalasia of the cardia in Allgrove's (triple A) syndrome: histopathologic study of 10 cases. Am. J. Surg. Pathol. 27, 667-672. doi: 10.1097/00000478-200305000-00010
77. Koh, S. D., Jun, J. Y., Kim, T. W., and Sanders, K. M. (2002). A Ca(2+)-inhibited non-selective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal. J. Physiol. 540, 803-814. doi: 10.1113/jphysiol.2001.014639
78. Koval, M., Isakson, B. E., and Gourdie, R. G. (2014). Connexins, pannexins and innexins: protein cousins with overlapping functions. FEBS Lett. 588, 1185. doi: 10.1016/j.febslet.2014.03.001
79. Kraichely, R. E., and Farrugia, G. (2007). Mechanosensitive ion channels in interstitial cells of Cajal and smooth muscle of the gastrointestinal tract. Neurogastroenterol. Motil. 19, 245-252. doi: 10.1111/j.1365-2982.2006.00880.x
80. Kreuzberg, M. M., Schrickel, J. W., Ghanem, A., Kim, J. S., Degen, J., Janssen-Bienhold, U., et al. (2006). Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node. Proc. Natl. Acad. Sci. U.S.A. 103, 5959-5964. doi: 10.1073/pnas.0508512103
81. Kwong, J. S., Leithäuser, B., Park, J. W., and Yu, C. M. (2013). Diagnostic value of magnetocardiography in coronary artery disease and cardiac arrhythmias: a review of clinical data. Int. J. Cardiol. 167, 1835-1842. doi: 10.1016/j.ijcard.2012.12.056
82. Lakatta, E. G., and DiFrancesco, D. (2009). JMCC Point-Counterpoint: what keeps us ticking, a funny current, a Calcium clock, or both? J. Mol. Cell. Cardiol. 47, 157-170. doi: 10.1016/j.yjmcc.2009.03.022
83. 2+ cycling and surface membrane ion channel activation entrains normal automaticity in cells of the heart's pacemaker. Ann. N.Y. Acad. Sci. 1080, 178-206. doi: 10.1196/annals.1380.016
84. Lammers, W. J., and Slack, J. R. (2001). Of slow waves and spike patches. News Physiol. Sci. 16, 138-144. doi: 10.1053/gast.2001.27713
85. Lammers, W. J., Slack, J. R., Stephen, B., and Pozzan, O. (2000). The spatial behaviour of spike patches in the feline gastroduodenal junction in vitro. Neurogastroenterol. Motil. 12, 467-473. doi: 10.1046/j.1365-2982.2000.00223.x
86. Lammers, W. J., and Stephen, B. (2008). Origin and propagation of individual slow waves along the intact feline small intestine. Exp. Physiol. 93, 334-346. doi: 10.1113/expphysiol.2007.039180
87. Lammers, W. J., Stephen, B., Adeghate, E., Ponery, S., and Pozzan, O. (1998). The slow wave does not propagate across the gastroduodenal junction in the isolated feline preparation. Neurogastroenterol. Motil. 10, 339-349. doi: 10.1046/j.1365-2982.1998.00113.x
88. Lammers, W. J., Stephen, B., Slack, J. R., and Dhanasekaran, S. (2002). Anisotropic propagation in the small intestine. Neurogastroenterol. Motil. 14, 357-364. doi: 10.1046/j.1365-2982.2002.00340.x
89. Lammers, W. J., Ver Donck, L., Stephen, B., Smets, D., and Schuurkes, J. A. (2009). Origin and propagation of the slow wave in the canine stomach: the outlines of a gastric conduction system. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1200-G1210. doi: 10.1152/ajpgi.90581.2008
90. Langer, J. C., Berezin, I., and Daniel, E. E. (1995). Hypertrophic pyloric stenosis: ultrastructural abnormalities of enteric nerves and the interstitial cells of Cajal. J. Pediatr. Surg. 30, 1535-1543. doi: 10.1016/0022-3468(95)90151-5
91. 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. U.S.A. 86, 7280-7284. doi: 10.1073/pnas.86.18.7280
92. Lee, H. T., Hennig, G. W., Fleming, N. W., Keef, K. D., Spencer, N. J., Ward, S. M., et al. (2007). The mechanism and spread of pacemaker activity through myenteric interstitial cells of cajal in human small intestine. Gastroenterology 132, 1852-1865. doi: 10.1053/j.gastro.2007.02.049
93. Lees-Green, R., Du, P., O'Grady, G., Beyder, A., Farrugia, G., and Pullan, A. J. (2011). Biophysically based modeling of the interstitial cells of cajal: current status and future perspectives. Front. Physiol. 2:29. doi: 10.3389/fphys.2011.00029
94. Leung, W. K., Lam, W. W., Wu, J. C., So, N. M., Fung, S. S., Chan, F. K., et al. (2004). Magnetic resonance colonography in the detection of colonic neoplasm in high-risk and average-risk individuals. Am. J. Gastroenterol. 99, 102-108. doi: 10.1046/j.1572-0241.2003.04008.x
95. Lin, A. S.-H., Buist, M. L., Smith, N. P., and Pullan, A. J. (2006). Modelling slow wave activity in the small intestine. J. Theor. Biol. 242, 356-362. doi: 10.1016/j.jtbi.2006.03.004
96. Lin, J., and Keener, J. P. (2013). Ephaptic coupling in cardiac myocytes. IEEE Trans. Biomed. Eng. 60, 576-582. doi: 10.1109/TBME.2012.2226720
97. Lyford, G. L., He, C. L., Soffer, E., Hull, T. L., Strong, S. A., Senagore, A. J., et al. (2002). Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation. Gut 51, 496-501. doi: 10.1136/gut.51.4.496
98. Maes, M., Cogliati, B., Crespo Yanguas, S., Willebrords, J., and Vinken, M. (2015). Roles of connexins and pannexins in digestive homeostasis. Cell. Mol. Life Sci. 72, 2809-2821. doi: 10.1007/s00018-015-1961-8
99. Maltsev, V. A., and Lakatta, E. G. (2013). Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca(2+) clock generate robust, flexible, and energy-efficient cardiac pacemaking. J. Mol. Cell. Cardiol. 59, 181-195. doi: 10.1016/j.yjmcc.2013.03.004
100. Manabe, N., Rao, A. S., Wong, B. S., and Camilleri, M. (2010). Emerging pharmacologic therapies for irritable bowel syndrome. Curr. Gastroenterol. Rep. 12, 408-416. doi: 10.1007/s11894-010-0124-1
101. Mazzini, E., Massimiliano, L., Penna, G., and Rescigno, M. (2014). Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 40, 248-261. doi: 10.1016/j.immuni.2013.12.012
102. McKay, C. M., Ye, J., and Huizinga, J. D. (2006). Characterization of depolarization-evoked ERG K currents in interstitial cells of Cajal. Neurogastroenterol. Motil. 18, 324-333. doi: 10.1111/j.1365-2982.2006.00764.x
103. Murakoshi, N., and Aonuma, K. (2013). Epidemiology of arrhythmias and sudden cardiac death in Asia. Circ. J. 77, 2419-2431. doi: 10.1253/circj.CJ-13-1129
104. Nerbonne, J. M., and Guo, W. (2002). Heterogeneous expression of voltage-gated potassium channels in the heart: roles in normal excitation and arrhythmias. J. Cardiovasc. Electrophysiol. 13, 406-409. doi: 10.1046/j.1540-8167.2002.00406.x
105. Nerbonne, J. M., and Kass, R. S. (2005). Molecular physiology of cardiac repolarization. Physiol. Rev. 85, 1205-1253. doi: 10.1152/physrev.00002.2005
106. Ng, S. C., Lam, E. F., Lam, T. T., Chan, Y., Law, W., Tse, P. C., et al. (2013). Effect of probiotic bacteria on the intestinal microbiota in irritable bowel syndrome. J. Gastroenterol. Hepatol. 28, 1624-1631. doi: 10.1111/jgh.12306
107. Nolasco, J. B., and Dahlen, R. W. (1968). A graphic method for the study of alternation in cardiac action potentials. J. Appl. Physiol. 25, 191-196.
108. O'Grady, G., Angeli, T. R., Du, P., Lahr, C., Lammers, W. J., Windsor, J. A., et al. (2012). Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping. Gastroenterology 143, 589-598 e581-e583. doi: 10.1053/j.gastro.2012.05.036
109. O'Grady, G., Wang, T. H., Du, P., Angeli, T., Lammers, W. J., and Cheng, L. K. (2014). Recent progress in gastric arrhythmia: pathophysiology, clinical significance and future horizons. Clin. Exp. Pharmacol. Physiol. 41, 854-862. doi: 10.1111/1440-1681.12288
110. Osadchii, O. E. (2014a). Impact of hypokalemia on electromechanical window, excitation wavelength and repolarization gradients in guinea-pig and rabbit hearts. PLoS ONE 9:e105599. doi: 10.1371/journal.pone.0105599
111. Osadchii, O. E. (2014b). Impaired epicardial activation-repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles. Acta Physiol. 211, 48-60. doi: 10.1111/apha.12259
112. Osadchii, O. E. (2016). Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart. Scand. Cardiovasc. J. 50, 28-35. doi: 10.3109/14017431.2015.1099721
113. 2+, and tension in intact smooth muscles. Am. J. Physiol. 260, C917-925.
114. Parsons, S. P., and Huizinga, J. D. (2015). Effects of gap junction inhibition on contraction waves in the murine small intestine in relation to coupled oscillator theory. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G287-G297. doi: 10.1152/ajpgi.00338.2014
115. Powley, T. L., Wang, X. Y., Fox, E. A., Phillips, R. J., Liu, L. W., and Huizinga, J. D. (2008). Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus. Neurogastroenterol. Motil. 20, 69-79. doi: 10.1111/j.1365-2982.2007.00990.x
116. Publicover, N. G., and Sanders, K. M. (1989). Are relaxation oscillators an appropriate model of gastrointestinal electrical activity? Am. J. Physiol. 256, G265-274.
117. Rhee, P. L., Lee, J. Y., Son, H. J., Kim, J. J., Rhee, J. C., Kim, S., et al. (2011). Analysis of pacemaker activity in the human stomach. J. Physiol. 589, 6105-6118. doi: 10.1113/jphysiol.2011.217497
118. Rhett, J. M., and Gourdie, R. G. (2012). The perinexus: a new feature of Cx43 gap junction organization. Heart Rhythm 9, 619-623. doi: 10.1016/j.hrthm.2011.10.003
119. Rhett, J. M., Veeraraghavan, R., Poelzing, S., and Gourdie, R. G. (2013). The perinexus: sign-post on the path to a new model of cardiac conduction? Trends Cardiovasc. Med. 23, 222-228. doi: 10.1016/j.tcm.2012.12.005
120. Robertson, J. D. (1963). The occurrence of a subunit pattern in the unit membranes of club endings in mauthner cell synapses in goldfish brains. J. Cell Biol. 19, 201-221. doi: 10.1083/jcb.19.1.201
121. Roden, D. M., Balser, J. R., George, A. L. J., and Anderson, M. E. (2002). Cardiac ion channels. Annu. Rev. Physiol. 64, 431-475. doi: 10.1146/annurev.physiol.64.083101.145105
122. Saez, J. C., Berthoud, V. M., Branes, M. C., Martinez, A. D., and Beyer, E. C. (2003). Plasma membrane channels formed by connexins: their regulation and functions. Physiol. Rev. 83, 1359-1400. doi: 10.1152/physrev.00007.2003
123. Saito, Y. A., Strege, P. R., Tester, D. J., Locke, G. R. III., Talley, N. J., Bernard, C. E., et al. (2009). Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G211-G218. doi: 10.1152/ajpgi.90571.2008
124. Sanders, K. M., Koh, S. D., and Ward, S. M. (2006). Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu. Rev. Physiol. 68, 307-343. doi: 10.1146/annurev.physiol.68.040504.094718
125. Sanders, K. M., and Vogalis, F. (1989). Organization of electrical activity in the canine pyloric canal. J. Physiol. 416, 49-66. doi: 10.1113/jphysiol.1989.sp017748
126. Sanders, K. M., Ward, S. M., and Koh, S. D. (2014). Interstitial cells: regulators of smooth muscle function. Physiol. Rev. 94, 859-907. doi: 10.1152/physrev.00037.2013
127. Sano, T., Takayama, N., and Shimamoto, T. (1959). Directional difference of conduction velocity in the cardiac ventricular syncytium studied by microelectrodes. Circ. Res. 7, 262-267. doi: 10.1161/01.RES.7.2.262
128. Sarna, S., Condon, R. E., and Cowles, V. (1983). Enteric mechanisms of initiation of migrating myoelectric complexes in dogs. Gastroenterology 84, 814-822.
129. Sato, Y., Yoshida, K., Ogata, K., Inaba, T., Tada, H., Sekiguchi, Y., et al. (2012). An increase in right atrial magnetic strength is a novel predictor of recurrence of atrial fibrillation after radiofrequency catheter ablation. Circ. J. 76, 1601-1608. doi: 10.1253/circj.CJ-11-1419
130. Schrickel, J. W., Kreuzberg, M. M., Ghanem, A., Kim, J. S., Linhart, M., Andrie, R., et al. (2009). Normal impulse propagation in the atrioventricular conduction system of Cx30.2/Cx40 double deficient mice. J. Mol. Cell. Cardiol. 46, 644-652. doi: 10.1016/j.yjmcc.2009.02.012
131. Schultz, T., Daniel, V., and Daniel, E. E. (2003). Does ICC pacing require functional gap junctions between ICC and smooth muscle in mouse intestine? Neurogastroenterol. Motil. 15, 129-138. doi: 10.1046/j.1365-2982.2003.00401.x
132. Seidel, S. A., Bradshaw, L. A., Ladipo, J. K., Wikswo, J. P. Jr., and Richards, W. O. (1999a). Noninvasive detection of ischemic bowel. J. Vasc. Surg. 30, 309-319. doi: 10.1016/S0741-5214(99)70142-4
133. Seidel, S. A., Hegde, S. S., Bradshaw, L. A., Ladipo, J. K., and Richards, W. O. (1999b). Intestinal tachyarrhythmias during small bowel ischemia. Am. J. Physiol. 277, G993-G999.
134. Seki, K., and Komuro, T. (2001). Immunocytochemical demonstration of the gap junction proteins connexin 43 and connexin 45 in the musculature of the rat small intestine. Cell Tissue Res. 306, 417-422. doi: 10.1007/s00441-001-0470-2
135. Sha, L., Farrugia, G., Harmsen, W. S., and Szurszewski, J. H. (2007). Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G438-G445. doi: 10.1152/ajpgi.00037.2007
136. Shafik, A., Ahmed, I., El Sibai, O., and Shafik, A. A. (2005). Interstitial cells of cajal in reflux esophagitis: role in the pathogenesis of the disease. Med. Sci. Monit. 11, BR452-BR456.
137. Siegle, M. L., and Ehrlein, H. J. (1987). Interdigestive contractile patterns of the ileum in dogs. Am. J. Physiol. Gastrointest. Liver Physiol. 253, G452-G460.
138. Sinagra, E., Pompei, G., Tomasello, G., Cappello, F., Morreale, G. C., Amvrosiadis, G., et al. (2016). Inflammation in irritable bowel syndrome: Myth or new treatment target? World J. Gastroenterol. 22, 2242-2255. doi: 10.3748/wjg.v22.i7.2242
139. Smith, T. K., Reed, J. B., and Sanders, K. M. (1987). Origin and propagation of electrical slow waves in circular muscle of canine proximal colon. Am. J. Physiol. Cell Physiol. 252, C215-C224.
140. Spach, M. S. (1999). Anisotropy of Cardiac Tissue. J. Cardiovasc. Electrophysiol. 10, 887-890. doi: 10.1111/j.1540-8167.1999.tb00271.x
141. Sperelakis, N., and McConnell, K. (2002). Electric field interactions between closely abutting excitable cells. IEEE Eng. Med. Biol. Mag. 21, 77-89. doi: 10.1109/51.993199
142. Steinhoff, U., Knappe-Grueneberg, S., Schnabel, A., Trahms, L., Smith, F., Langley, P., et al. (2004). Magnetocardiography for pharmacology safety studies requiring high patient throughput and reliability. J. Electrocardiol. 37(Suppl.), 187-192. doi: 10.1016/j.jelectrocard.2004.08.055
143. Strege, P. R., Ou, Y., Sha, L., Rich, A., Gibbons, S. J., Szurszewski, J. H., et al. (2003). Sodium current in human intestinal interstitial cells of Cajal. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G1111-G1121. doi: 10.1152/ajpgi.00152.2003
144. Struijs, M.-C., Diamond, I. R., Pencharz, P. B., Chang, K. T. E., Viero, S., Langer, J. C., et al. (2008). Absence of the interstitial cells of Cajal in a child with chronic pseudoobstruction. J. Pediatr. Surg. 43, e25-e29. doi: 10.1016/j.jpedsurg.2008.09.017
145. Suzuki, H., and Hirst, G. D. S. (1999). Regenerative potentials evoked in circular smooth muscle of the antral region of guinea-pig stomach. J. Physiol. 517, 563-573. doi: 10.1111/j.1469-7793.1999.0563t.x
146. Suzuki, H., Takano, H., Yamamoto, Y., Komuro, T., Saito, M., Kato, K., et al. (2000). Properties of gastric smooth muscles obtained from mice which lack inositol trisphosphate receptor. J. Physiol. 525(Pt 1), 105-111. doi: 10.1111/j.1469-7793.2000.00105.x
147. Suzuki, N., Prosser, C. L., and Dahms, V. (1986). Boundary cells between longitudinal and circular layers: essential for electrical slow waves in cat intestine. Am. J. Physiol. 250, G287-G294.
148. Szurszewski, J. H., Elveback, L. R., and Code, C. F. (1970). Configuration and frequency gradient of electric slow wave over canine small bowel. Am. J. Physiol. 218, 1468-1473.
149. Takaki, M., Suzuki, H., and Nakayama, S. (2010). Recent advances in studies of spontaneous activity in smooth muscle: ubiquitous pacemaker cells. Prog. Biophys. Mol. Biol. 102, 129-135. doi: 10.1016/j.pbiomolbio.2010.05.007
150. Tana, C., Umesaki, Y., Imaoka, A., Handa, T., Kanazawa, M., and Fukudo, S. (2010). Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol. Motil. 22, e512-e115. doi: 10.1111/j.1365-2982.2009.0142
151. Thorneloe, K. S., and Nelson, M. T. (2005). Ion channels in smooth muscle: regulators of intracellular calcium and contractility. Can. J. Physiol. Pharmacol. 83, 215-242. doi: 10.1139/y05-016
152. Tse, G. (2015). Mechanisms of Cardiac Arrhythmias. J. Arrhythmia 32, 75-81. doi: 10.1016/j.joa.2015.11.003
153. Tse, G. (2016a). Both transmural dispersion of repolarization and transmural dispersion of refractoriness are poor predictors of arrhythmogenicity: a role for the index of cardiac electrophysiological balance (QT/QRS)? J. Geriatr. Cardiol.
154. Tse, G. (2016b). Novel indices for stratifying arrhythmic risk: (Tpeak-Tend)/QRS and (Tpeak-Tend)/(QT x QRS). J. Geriatr. Cardiol.
155. Tse, G. (2016c). (Tpeak-Tend)/QRS and (Tpeak-Tend)/(QT x QRS): novel markers for predicting arrhythmic risk in Brugada syndrome. Europace.
156. Tse, G., Ali, A., Alpendurada, F., Prasad, S., Raphael, C. E., and Vassiliou, V. (2015a). Tuberculous constrictive pericarditis. Res. Cardiovasc. Med. 4:e29614. doi: 10.5812/cardiovascmed.29614
157. Tse, G., Ali, A., Prasad, S. K., Vassiliou, V., and Raphael, C. E. (2015b). Atypical case of post-partum cardiomyopathy: an overlap syndrome with arrhythmogenic right ventricular cardiomyopathy? BJR Case Rep. 1:20150182. doi: 10.1259/bjrcr.20150182
158. Tse, G., Hothi, S. S., Grace, A. A., and Huang, C. L. (2012). Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts. J. Physiol. Sci. 62, 79-92. doi: 10.1007/s12576-011-0187-2
159. Tse, G., Lai, E. T., Tse, V., and Yeo, J. M. (2016a). Molecular and electrophysiological mechanisms underlying cardiac arrhythmogenesis in diabetes mellitus. J. Diab. Res.
160. Tse, G., Lai, E. T., Yeo, J. M., and Yan, B. P. (2016b). Electrophysiological mechanisms of Bayés syndrome: insights from clinical and mouse studies. Front. Physiol. 7:188. doi: 10.3389/fphys.2016.00188
161. Tse, G., Tse, V., and Yeo, J. M. (2016c). Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts. Biomed. Rep. 4, 313-324. doi: 10.3892/br.2016.577
162. Tse, G., Tse, V., Yeo, J. M., and Sun, B. (2016d). Atrial anti-arrhythmic effects of heptanol in Langendorff-perfused mouse hearts. PLoS ONE 11:e0148858. doi: 10.1371/journal.pone.0148858
163. Tse, G., Wong, S. T., Tse, V., Lee, Y. T., Lin, H. Y., and Yeo, J. M. (2016e). Cardiac dynamics: alternans and arrhythmogenesis. J. Arrhythmia. doi: 10.1016/j.joa.2016.02.009. [Epub ahead of print].
164. Tse, G., Wong, S. T., Tse, V., and Yeo, J. M. (2016f). Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts? Acta Physiol. doi: 10.1111/apha.12694
165. Tse, G., Wong, S. T., Tse, V., and Yeo, J. M. (2016g). Determination of action potential wavelength restitution in Scn5a+/-mouse hearts modelling human Brugada syndrome. J. Physiol.
166. Tse, G., Wong, S. T., Tse, V., and Yeo, J. M. (2016h). Monophasic action potential recordings: which is the recording electrode? J. Basic Clin. Physiol. Pharmacol. doi: 10.1515/jbcpp-2016-0007. [Epub ahead of print].
167. Tse, G., Wong, S. T., Tse, V., and Yeo, J. M. (2016i). Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts. Biomed. Rep. 4, 673-680. doi: 10.3892/br.2016.659
168. Tse, G., and Yan, B. P. (2016). Novel arrhythmic risk markers incorporating QRS dispersion: QRSd x (Tpeak-Tend)/QRS and QRSd x (Tpeak-Tend)/(QT x QRS). Ann. Noninvasive. Electrocardiol.
169. Tse, G., and Yeo, J. M. (2015). Conduction abnormalities and ventricular arrhythmogenesis: the roles of sodium channels and gap junctions. IJC Heart Vascul. 9, 75-82. doi: 10.1016/j.ijcha.2015.10.003
170. Vanderwinden, J. M., Liu, H., De Laet, M. H., and Vanderhaeghen, J. J. (1996). Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis. Gastroenterology 111, 279-288. doi: 10.1053/gast.1996.v111.pm8690192
171. van Helden, D. F., Laver, D. R., Holdsworth, J., and Imtiaz, M. S. (2010). Generation and propagation of gastric slow waves. Clin. Exp. Pharmacol. Physiol. 37, 516-524. doi: 10.1111/j.1440-1681.2009.05331.x
172. Vassiliou, V., Chin, C., Perperoglou, A., Tse, G., Ali, A., Raphael, C., et al. (2014). 93 Ejection fraction by cardiovascular magnetic resonance predicts adverse outcomes post aortic valve replacement. Heart 100, A53-A54. doi: 10.1136/heartjnl-2014-306118.93
173. Veeraraghavan, R., Gourdie, R. G., and Poelzing, S. (2014a). Mechanisms of cardiac conduction: a history of revisions. Am. J. Physiol. Heart Circ. Physiol. 306, H619-H627. doi: 10.1152/ajpheart.00760.2013
174. Veeraraghavan, R., Lin, J., Hoeker, G. S., Keener, J. P., Gourdie, R. G., and Poelzing, S. (2015). Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study. Pflugers Arch. 467, 2093-2105. doi: 10.1007/s00424-014-1675-z
175. Veeraraghavan, R., Poelzing, S., and Gourdie, R. G. (2014b). Intercellular electrical communication in the heart: a new, active role for the intercalated disk. Cell Commun. Adhes. 21, 161-167. doi: 10.3109/15419061.2014.905932
176. Veeraraghavan, R., Poelzing, S., and Gourdie, R. G. (2014c). Novel ligands for zipping and unzipping the intercalated disk: today's experimental tools, tomorrow's therapies? Cardiovasc. Res. 104, 229-230. doi: 10.1093/cvr/cvu216
177. Veeraraghavan, R., Poelzing, S., and Gourdie, R. G. (2014d). Old cogs, new tricks: a scaffolding role for connexin43 and a junctional role for sodium channels? FEBS Lett. 588, 1244-1248. doi: 10.1016/j.febslet.2014.01.026
178. Verheule, S., and Kaese, S. (2013). Connexin diversity in the heart: insights from transgenic mouse models. Front. Pharmacol. 4:81. doi: 10.3389/fphar.2013.00081
179. Vigmond, E. J. (2005). The electrophysiological basis of MAP recordings. Cardiovasc. Res. 68, 502-503. doi: 10.1016/j.cardiores.2005.07.020
180. Vigmond, E. J., and Bardakjian, B. L. (1995). The effect of morphological interdigitation on field coupling between smooth muscle cells. IEEE Trans. Biomed. Eng. 42, 162-171. doi: 10.1109/10.341829
181. Vigmond, E. J., and Leon, L. J. (1999). Electrophysiological basis of mono-phasic action potential recordings. Med. Biolog. Eng. Comput. 37, 359-365. doi: 10.1007/BF02513313
182. Vigmond, E. J., Tsoi, V., Yin, Y., Pagé, P., and Vinet, A. (2009). Estimating atrial action potential duration from electrograms. IEEE Trans. Biomed. Eng. 56, 1546-1555. doi: 10.1109/TBME.2009.2014740
183. 2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick. Ann. N.Y. Acad. Sci. 1047, 138-156. doi: 10.1196/annals.1341.013
184. Walker, R. L., Koh, S. D., Sergeant, G. P., Sanders, K. M., and Horowitz, B. (2002). TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am. J. Physiol Cell Physiol. 283, C1637-C1645. doi: 10.1152/ajpcell.00266.2002
185. Wang, X. Y., Lammers, W. J., Bercik, P., and Huizinga, J. D. (2005). Lack of pyloric interstitial cells of Cajal explains distinct peristaltic motor patterns in stomach and small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G539-G549. doi: 10.1152/ajpgi.00046.2005
186. 2+ uptake in canine colonic muscles. J. Physiol. 549, 207-218. doi: 10.1113/jphysiol.2003.040097
187. 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(Pt 1), 91-97. doi: 10.1113/jphysiol.1994.sp020343
188. Ward, S. M., Ordog, T., Koh, S. D., Baker, S. A., Jun, J. Y., Amberg, G., et al. (2000). Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J. Physiol. 525(Pt 2), 355-361. doi: 10.1111/j.1469-7793.2000.t01-1-00355.x
189. Watanuki, S., Ogata, H., Yokoyama, H., Kaiho, M., Honda, M., Ono, K., et al. (1969). Electrophysiological studies on congenital pyloric stenosis. Jpn. J. Smooth Muscle Res. 5, 117-125. doi: 10.1540/jsmr1965.5.117
190. Weber, P. A., Chang, H.-C., Spaeth, K. E., Nitsche, J. M., and Nicholson, B. J. (2004). The permeability of gap junction channels to probes of different size is dependent on connexin composition and permeant-pore affinities. Biophys. J. 87, 958-973. doi: 10.1529/biophysj.103.036350
191. Weidmann, S. (1952). The electrical constants of Purkinje fibres. J. Physiol. 118, 348-360. doi: 10.1113/jphysiol.1952.sp004799
192. Weisbrodt, N. W. (1981). Patterns of intestinal motility. Annu. Rev. Physiol. 43, 21-31. doi: 10.1146/annurev.ph.43.030181.000321
193. Won, K. J., Sanders, K. M., and Ward, S. M. (2005). Interstitial cells of Cajal mediate mechanosensitive responses in the stomach. Proc. Natl. Acad. Sci. U.S.A. 102, 14913-14918. doi: 10.1073/pnas.0503628102
194. Yamataka, A., Kato, Y., Tibboel, D., Murata, Y., Sueyoshi, N., Fujimoto, T., et al. (1995). A lack of intestinal pacemaker (c-kit) in aganglionic bowel of patients with Hirschsprung's disease. J. Pediatr. Surg. 30, 441-444. doi: 10.1016/0022-3468(95)90051-9
195. Yaniv, Y., Lyashkov, A. E., Sirenko, S., Okamoto, Y., Guiriba, T. R., Ziman, B. D., et al. (2014). Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. J. Mol. Cell. Cardiol. 77, 1-10. doi: 10.1016/j.yjmcc.2014.09.008
196. Yeo, Q. M., Crutchley, R., Cottreau, J., Tucker, A., and Garey, K. W. (2013). Crofelemer, a novel antisecretory agent approved for the treatment of HIV-associated diarrhea. Drugs Today 49, 239-252. doi: 10.1358/dot.2013.49.4.1947253
197. Yoshida, K., Ogata, K., Inaba, T., Nakazawa, Y., Ito, Y., Yamaguchi, I., et al. (2015). Ability of magnetocardiography to detect regional dominant frequencies of atrial fibrillation. J. Arrhythm 31, 345-351. doi: 10.1016/j.joa.2015.05.003
198. Yoshida, K., Tada, H., Ogata, K., Sekiguchi, Y., Inaba, T., Ito, Y., et al. (2012). Electrogram organization predicts left atrial reverse remodeling after the restoration of sinus rhythm by catheter ablation in patients with persistent atrial fibrillation. Heart Rhythm 9, 1769-1778. doi: 10.1016/j.hrthm.2012.06.033
199. Zhu, M. H., Kim, T. W., Ro, S., Yan, W., Ward, S. M., Koh, S. D., et al. (2009). A Ca(2+)-activated Cl(-) conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J. Physiol. 587, 4905-4918. doi: 10.1113/jphysiol.2009.176206
200. Zhu, Y., and Huizinga, J. D. (2008). Nitric oxide decreases the excitability of interstitial cells of Cajal through activation of the BK channel. J. Cell. Mol. Med. 12, 1718-1727. doi: 10.1111/j.1582-4934.2008.00217.x