Abstract
Inflammation markedly alters the motility patterns of the gastrointestinal tract, resulting mostly in decreased excitability of smooth muscle. There is emerging evidence indicating that inflammation alters ion channel expression and function of smooth muscle cells. In this review we summarize studies defining the mechanisms affecting contractile and electrical activity of gastrointestinal smooth muscle. We have focused on the evidence for decreased calcium channel conductance and alterations in the intracellular signaling mechanisms and discuss the role of muscarinic receptor activation in models of gastrointestinal inflammation. We propose that some of the clinical symptoms of altered smooth muscle contraction in pathogenesis of gut disorders such as inflammatory bowel disease may be regulated at the level of the ion channel.
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Waxman, S. G. (2001) Transcriptional channelopathies: an emerging class of disorders. Nat. Rev. Neurosci. 2, 652–659.
Horowitz, B., Ward, S. M., and Sanders, K. M. (1999) Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu. Rev. Physiol. 61, 19–43.
Huizinga, J. D. (1999) Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal. Microsc. Res. Tech. 47, 239–247.
Murthy, K. S., Grider, J. R., Jin, J. G., and Makhlouf, G. M. (1995) Interplay of VIP and nitric oxide in the regulation of neuromuscular activity in the gut. Arch. Int. Pharmacodyn. Ther. 329, 27–38.
Vermillion, D. L., Huizinga, J. D., Riddell, R. H., and Collins, S. M. (1993) Altered small-intestinal smooth-muscle function in Crohns-disease. Gastroenterology 104, 1692–1699.
Cohen, J. D., Kao, H. W., Tan, S. T., Lechago, J., and Snape, W. J., Jr. (1986) Effect of acute experimental colitis on rabbit colonic smooth muscle. Am. J. Physiol. 251, G538-G545.
Wells, R. W., Morris, G. P., Blennerhassett, M. G., and Paterson, W. G. (2003) Effects of acid-induced esophagitis on esophageal smooth muscle. Can. J. Physiol. Pharmacol. 81, 451–458.
White, R. J., Zhang, Y., Morris, G. P., and Paterson, W. G. (2001) Esophagitis related esophageal shortening in opossum is associated with longitudinal muscle hyperresponsiveness. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G463-G469.
Sarna, S. K. (2003) Neuronal locus and cellular signaling for stimulation of ileal giant migrating and phasic contractions. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G789-G797.
Ward, S. M., Keller, R. G., and Sanders, K. M. (1991) Structure and organization of electrical activity of canine distal colon. Am. J. Physiol. 260, G724-G735.
Huizinga, J. D. and Barajas-Lopez, C. (1990) Ionic and cellular basis for slowwave-type and spike-like action potentials. Prog. Clin. Biol. Res. 327, 605–615.
Szurszewski J. H. (1969) A migrating electric complex of canine small intestine. Am. J. Physiol. 217, 1757–1763.
Sarna, S. K. (1985) Cyclic motor activity; migrating motor complex: 1985. Gastroenterology 89, 894–913.
Sarna, S. K. (1991) MMC migration: neural or muscular?. Am. J. Physiol. 260, G665-G667.
Spencer, N. J., Sanders, K. M., and Smith, T. K. (2003) Migrating motor complexes do not require electrical slow waves in the mouse small intestine. J. Physiol. 553, 881–893.
Kern, F., Jr., Almy, T. P., Abbot, F. K., and Bogdonoff, M. D. (1951) The motility of the distal colon in non-specific ulcerative colitis. Gastroenterology 19, 492–503.
Sarna, S. K. (1998) In vivo signal-transduction pathways to stimulate phasic contractions in normal and inflamed ileum. Am. J. Physiol. 274, G618-G625.
Biancani, P., Sohn, U. D., Rich, H. G., Harnett, K. M., and Behar, J. (1997) Signal transduction pathways in esophageal and lower esophageal sphincter circular muscle. Am. J. Med. 103, 23S-28S.
Chey, W. Y., Jin, H. O., Lee, M. H., Sun, S. W., and Lee, K. Y. (2001) Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am. J. Gastroenterol. 96, 1499–1506.
Kern, S. E., Redston, M., Seymour, A. B., Caldas, C., Powell, S. M., Kornacki, S., et al. (1994) Molecular genetic profiles of colitis-associated neoplasms. Gastroenterology 107, 420–428.
Lind, C. D. (1991) Motility disorders in the irritable bowel syndrome. Gastroenterol. Clin. North Am. 20, 279–295.
Reddy, S. N., Bazzocchi, G., Chan, S., Akashi, K., Villanuevameyer, J., Yanni, G., et al. (1991) Colonic motility and transit in health and ulcerative-colitis. Gastroenterology 101, 1289–1297.
Li, M., Johnson, C. P., Adams, M. B., and Sarna, S. K. (2002) Cholinergic and nitrergic regulation of in vivo giant migrating contractions in rat colon. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G544-G552.
Shi, X. Z. and Sarna, S. K. (1999) Differential inflammatory modulation of canine ileal longitudinal and circular muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 277, G341-G350.
Akiho, H., Blennerhassert, P., Deng, Y., and Collins, S. M. (2002) Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G226-G232.
Szurszewski, J. H. (1985) Smooth muscle physiology. Nippon Heikatsukin. Gakkai Zasshi 21, Suppl. 1.
Moreels, T. G., De Man, J. G., Dick, J. M., Nieuwendijk, R. J., De Winter, B. Y., Lefebvre, et al. (2001) Effect of TNBS induced morphological changes on pharmacological contractility of the rat ileum. Eur. J. Pharmacol. 423, 211–222.
Lu, G., Qian, X., Berezin, I., Telford, G. L., Huizinga, J. D., and Sarna, S. K. (1997) Inflammation modulates in vitro colonic myoelectric and contractile activity and interstitial cells of Cajal. Am. J. Physiol. 273, G1233-G1245.
Koch, T. R., Carney, J. A., Go, V. L., and Szurszewski, J. H. (1991) Inhibitory neuropeptides and intrinsic inhibitory innervation of descending human colon. Dig. Dis. Sci. 36, 712–718.
Rasmussen, H. H., Fallingborg, J. F., Mortensen, P. B., Vyberg, M., Tage-Jensen, U., and Rasmussen, S. N. (1997) Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn's disease. Scand. J. Gastroenterol. 32, 604–610.
Akbarali, H. I., Pothoulakis, C., and Castagliuolo, I. (2000) Altered ion channel activity in murine colonic smooth muscle myocytes in an experimental colitis model. Biochem. Biophys. Res. Commun. 275, 637–642.
Liu, X., Rusch, N. J., Striessnig, J., and Sarna, S. K. (2001) Down-regulation of L-type calcium channels in inflamed circular smooth muscle cells of the canine colon. Gastroenterology 120, 480–489.
Kinoshita, K., Sato, K., Hori, M., Ozaki, H., and Karaki, H. (2003) Decrease in the activity of the L-type Ca2+-channels and its reversal by NF-κB inhibitors in colonic smooth muscle isolated from a TNBS-induced colitis model rat. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G483-G493.
Soldatov, N. M. (2003) Ca2+ channel moving tail; link between Ca2+-induced inactivation and Ca2+ signal transduction. Trends Pharmacol. Sci. 24, 167–171.
Koch, W. J., Hui, A., Shull, G. E., Ellinor, P., and Schwartz, A. (1989) Characterization of cDNA clones encoding two putative isoforms of the alpha 1 subunit of the dihydropyridine-sensitive voltage-dependent calcium channel isolated from rat brain and rat aorta. FEBS Lett. 250, 386–388.
Dai, B., Saada, N., Echetebu, C., Dettbam, C., and Palade, P. (2002) A new promoter for alpha1C subunit of human L-type cardiac calcium channel Ca(V)1.2. Biochem. Biophys. Res. Commun. 296, 429–433.
Holm, A. N., Rich, A., Sarr, M. G., and Farrugia, G. (2000) Whole cell current and membrane potential regulation by a human smooth muscle mechanosensitive calcium channel. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1155-G1161.
Saada, N., Dai, B., Echetebu, C., Sarna, S. K., and Palade, P. (2003) Smooth muscle uses another promoter to express primarily a form of human Cav1.2 L type calcium channel different from the principll heart form. Biochem. Biophys. Res. Commun. 302, 23–28.
Neurath, M. F., Fuss, I., Schurmann, G., Pettersson, S., Arnold, K., Muller-Lobeck, H., et al. (1998) Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann. N. Y. Acad. Sci. 859, 149–159.
Ghosh, S., May, M. J., and Kopp, E. B. (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260.
Shi, X. Z., Lindholm, P. F., and Sarna, S. K. (2003) NF-kappa B activation by oxidative stress and inflammation suppresses contractility in colonic circular smooth muscle cells. Gastroenterology 124, 1369–1380.
Stevenson, A. S., Gomez, M. F., Hill-Eubanks, D. C., and Nelson, M. T. (2001) NFAT4 movement in native smooth muscle. A role for differential Ca(2+) signaling. J Biol. Chem. 276, 15018–15024.
Gomez, M. F., Gonzalez Bosc, L. V., Stevenson, A. S., Wilkerson, M. K., Hill-Eubanks, D. C., and Nelson, M. T. (2003) Constitutively elevated nuclear export activity opposes Ca2+-dependent NFATc3 nuclear accumulation in vascular smooth muscle: role of JNK2 and Crm-1. J. Biol. Chem. 278, 46847–46853.
Hu, X. Q., Singh, N., Mukhopadhyay, D., and Akbarali, H. I. (1998) Modulation of voltage-dependent Ca2+ channels in rabbit colonic smooth muscle cells by c-Src and focal adhesion kinase. J. Biol. Chem. 273, 5337–5342.
Hatakaeyama, N., Mukhopadhyay, D., Goyal, R. K., and Akbarali, H. I. (1996) eyrosine kinase-dependent modulation of calcium entry in rabbit colonic muscularis mucosae. Am. J. Physiol. 270, C1780-C1789.
Davis, M. J., Wu, X., Nurkiewicz, T. R., Kawasaki, J., Gui, P., Hill, M. A., and Wilson, E., (2002) Regulation of ion channels by integrins. Cell Biochem. Biophys. 36, 41–66.
Di Salyo, J., Nelson, S. R., and Kaplan, N. (1997) Protein tyrosine phosphorylation in smooth muscle: a potential coupling mechanism between receptor activation and intracellular calcium. Proc. Soc. Exp. Biol. Med. 214, 285–301.
Hollenberg, M. D. (1994) Tyrosine kinase pathways and the regulation of smooth muscle contractility. Trends Pharmacol. Sci. 15, 108–114.
Bence-Hanulec, K. K., Marshall, J., and Blair, L. A. (2000) Potentiation of neuronal L calcium channels by IGF-1 requires phosphorylation of the alpha1 subunit on a specific tyrosine residue. Neuron 27, 121–131
Jin, X., Morsy, N., Shoeb, F., Zavzavadjian, J., and Akbarali, H. I. (2002) Coupling of M2 muscarinic receptor to L-type Ca channel via c-src kinase in rabbit colonic circular smooth muscle. Gastroenterology 123, 827–834.
Babenko, A. P., Aguilar-Bryan, L., and Bryan, J. (1998) A view of sur/KIR6X, KATP channels. Annu. Rev. Physiol. 60, 667–687
Seino, S. (1999) ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu. Rev. Physiol. 61, 337–362.
Hatakeyama, N., Wang, Q., Goyal, R. K., and Akbarali, H. I. (1995) Muscarinic suppression of ATP-sensitive K+ channel in rabbit esophageal smooth muscle. Am. J. Physiol. 268, C877-C885.
Akbarali H. I. and Jin X. (2003) ATP-sensitive K+ channels demonstrate enhanced bursting activity in a murine experimental colitis model. Gastroenterology 124, S1022.
Preiksaitis, H. G., Krysiak, P. S., Chrones, T., Rajgopal, V., and Laurier, L. G. (2000) Pharmacological and molecular characterization of muscarinic receptor subtypes in human esophageal smooth muscle. J. Pharmacol. Exp. Ther. 295, 879–888.
Wang, J., Krysiak, P. S., Laurier, L. G., Sims, S. M., and Preiksaitis, H. G. (2000) Human esophageal smooth muscle cells express muscarinic receptor subtypes M(1) through M(5). Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1059-G1069.
Stengel, P. W., Yamada, M., Wess, J., and Cohen, M. L. (2002) M(3)-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1443-R1449.
Matsui, M., Motomura, D., Fujikawa, T., Jiang, J., Takahashi, S., Manabe, T., et al. (2002) Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J. Neurosci. 22, 10627–10632.
Sawyer, G. W. and Ehlert, F. J. (1999) Muscarinic M3 receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea pig colon: evidence for M2/M3 receptor interactions. J. Pharmacol. Exp. Ther. 289, 464–476.
Bolton, T. B. (1979) Cholinergic mechanisms in smooth muscle. Br. Med. Bull. 35, 275–283.
Inoue, M. and Kuriyama, H. (1991) Muscarinic receptor is coupled with a cation channel through a GTP-binding protein in guinea-pig chromaffin cells. J. Physiol. 436, 511–529.
Inoue, R. and Isenberg, G. (1990) Acetylcholine activates nonselective cation channels in guinea pig ileum through a G protein. Am. J. Physiol. 258, C1173-C1178.
Pacaud, P. and Bolton, T. B. (1991) Relation between muscarinic receptor cationic current and internal calcium in guinea-pig jejunal smooth muscle cells. J. Physiol. 441, 477–499.
Kotlikoff, M. I., Dhulipala, P., and Wang, Y. X. (1999) M2 signaling in smooth muscle cells. Life Sci. 64, 437–442.
Wang, Y. X., Dhulipala, P. D., Li, L., Benovic, J. L., and Kotlikoff, M. I. (1999) Coupling of M2 muscarinic receptors to membrane ion channels via phosphoinositide 3-kinase gamma and atypical protein kinase C. J. Biol. Chem. 274, 13859–13864.
Shi, X. Z. and Sarna, S. K. (1997) Inflammatory modulation of muscarinic receptor activation in canine ileal circular muscle cells. Gastroenterology 112, 864–874.
Ehlert, F. J., Sawyer, G. W., and Esqueda, E. E. (1999) Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle. Life Sci. 64, 387–394.
Jadcherla, S. R. (2002) Inflammatory inhibits muscarinic signaling in in vivo canine colonic circular smooth muscle cells. Pediatr. Res. 52, 756–762.
Murthy, K. S. and Makhlouf, G. M. (1997) Differential coupling of muscarinic m2 and m3 receptors to adenylyl cyclases V/VI in smooth muscle. Concurrent M2-mediated inhibition via Galphai3 and m3-mediated stimulation via Gbetagammaq. J. Biol. Chem. 272, 21317–21324.
Murthy, K. S. and Makhlouf, G. M. (1998) Regulation of adenylyl cyclase type V/VI in smooth muscle: interplay of inhibitory G protein and Ca2+ influx. Mol. Pharmacol. 54, 122–128.
Sohn, U. D., Harnett, K. M., Cao, W., Rich, H., Kim, N., Behar, J., et al. (1997) Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter. J. Pharmacol. Exp. Ther. 283, 1293–1304.
Singer, C. A., Vang, S., and Gerthoffer, W. T. (2002) Coupling of M(2) muscarinic receptors to Src activation in cultured canine colonic smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G61-G68.
Gold, M. S. (1999) Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia. Proc. Natl. Acad. Sci. U. S. A. 96, 7645–7649.
Lai, J., Gold, M. S., Kim, C. S., Bian, D., Ossipov, M. H., Hunter, J. C., et al. (2002) Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95, 143–152.
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Malykhina, A.P., Akbarali, H.I. Inflammation-induced “Channelopathies” in the gastrointestinal smooth muscle. Cell Biochem Biophys 41, 319–330 (2004). https://doi.org/10.1385/CBB:41:2:319
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DOI: https://doi.org/10.1385/CBB:41:2:319