Regulation of Epithelial Chloride Channels: Roles of Protein Kinases and Arachidonic Acid

  • Tzyh-Chang Hwang
  • William B. Guggino
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 290)


Epithelial Cl- secretion plays a crucial role in controlling the content of airway fluid. The quantity and composition of airway fluid determine the effectiveness of mucociliary clearance, one of the natural lung defense mechanisms that protect the respiratory system from infection. Transcellular Cl- secretion accompanied by Na+ provides the osmotic force for water flow which hydrates the mucous coating on the surface of epithelia (see ref 1 for review).


Cystic Fibrosis Arachidonic Acid Chloride Channel Ricinoleic Acid Tracheal Epithelium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Welsh, M.J., 1987, Electrolyte transport by airway epithelia, Physiol. Rev., 67:1143.PubMedGoogle Scholar
  2. 2.
    Al-Bazzaz, F., Cheng, E., 1979, Effect of catecholamines on ion transport in dog tracheal epithelium, J. Appl. Physiol., 47:397.PubMedGoogle Scholar
  3. 3.
    Boucher, R.C., Gatzy, J.T., 1982, Regional effects of autonomic agents on ion transport across excised canine airways, J. Appl. Physiol., 52:893.PubMedGoogle Scholar
  4. 4.
    Davis, B., Marin, M.G., Yee, J.W., Nadel, J.A.,1979, Effect of terbutaline on movement of Cl-and Na+ across the trachea of the dog in vitro, Am. Rev. Respir. Dis., 120:547.PubMedGoogle Scholar
  5. 5.
    Lazarus, S.C., Basbaum, C.B., Gold, W.M., 1984, Localization of cAMP in dog and cat trachea: effects of β-adrenergic agonists, Am. J. Physiol., 247:C327.PubMedGoogle Scholar
  6. 6.
    Liedtke, C.M., Tandler, B., 1984, Physiological responsiveness of isolated rabbit tracheal epithelial cells, Am. J. Physiol., 247:C441.PubMedGoogle Scholar
  7. 7.
    Smith, P.L. Welsh, M.J., Stoff, J.W., Frizzell, R.A., 1982, Chloride secretion by canine tracheal epithelium. I. Role of intracellular cAMP levels, J. Membr. Biol., 70:217.PubMedCrossRefGoogle Scholar
  8. 8.
    Welsh, M.J., 1986, Adrenergic regulation of ion transport by primary cultures of canine tracheal epithelium: cellular electrophysiology, J. Membr. Biol., 91:121.PubMedCrossRefGoogle Scholar
  9. 9.
    Al-Bazzaz, F.J., 1981, Role of cyclic AMP in regulation of chloride secretion by canine tracheal mucosa, Am. Rev. Respir. Dis., 123:295.PubMedGoogle Scholar
  10. 10.
    Al-Bazzaz, F. J., Yadava, V.P., Westen-Felder, C., 1981, Modification of Na+ and Cl-transport in canine tracheal mucosa by prostaglandins, Am. J. Physiol., 240:F101.PubMedGoogle Scholar
  11. 11.
    Liedtke, C.M., Boat, T.F., Rudolph, S.A., 1982, Neurohormo-7. nal receptors and cyclic AMP-binding proteins in rabbit tracheal mucosa-submucosa, Biochim. Biophys. Acta 719:169.PubMedCrossRefGoogle Scholar
  12. 12.
    Barthelson, R.A., Jacoby, D.B., Widdicombe, J.H., 1987, Regulation of chloride secretion in dog tracheal epithelium by protein kinase C, Am. J. Physiol., 253:C802.PubMedGoogle Scholar
  13. 13.
    Welsh, M.J., 1987, Effect of phorbol ester and calcium ionophore on chloride secretion in canine tracheal epithelium, Am-J. Physiol., 253:C828.PubMedGoogle Scholar
  14. 14.
    Eling, T.E., Danilowicz, R.M., Henke, D.C., 1986, Arachidonic acid metabolism by canine tracheal epithelial cells. Product formation and relationship to chloride secretion, J. Biol. Chem., 261:12841.PubMedGoogle Scholar
  15. 15.
    Quinton, P.M., 1983, Chloride impermeability in cystic fibrosis. Nature 301:421.PubMedCrossRefGoogle Scholar
  16. 16.
    Knowles, M., Gatzy, J., Boucher, R., 1981, Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis, N. Engl. J. Med., 305:1489.PubMedCrossRefGoogle Scholar
  17. 17.
    Knowles, M., Gatzy, J., Boucher, R., 1983, Relative ion permeability of normal and cystic fibrosis nasal epithelium, J. Clin. Invest., 71:1410.PubMedCrossRefGoogle Scholar
  18. 18.
    Knowles, M.R., Stutts, M.J., Spock, A., 1983, Abnormal ion permeation through cystic fibrosis respiratory epithelium, Science, 221:1067.PubMedCrossRefGoogle Scholar
  19. 19.
    Berschneider, H.M., Knowles, M.R., Azizkhan, R.G., 1988, Altered intestinal chloride transport in cystic fibrosis, FASEB J., 2:2625.PubMedGoogle Scholar
  20. 20.
    Widdicombe, J.H., Welsh, M.J., Finkbeiner, W.E., 1985, Cystic fibrosis decreases the apical membrane chloride permeability of monolayer cultured from cells of tracheal epithelium, Proc. Natl. Acad. Sci., 82:6167.PubMedCrossRefGoogle Scholar
  21. 21.
    Yankaskas, J.R., Cotton, C.U., Knowles, M.R., 1985, Culture of human nasal epithelial cells on collagen matrix support: a comparison of bioelectric properties of normal and cystic fibrosis epithelia, Am. Rev. Respir. Dis. 132:1281.PubMedGoogle Scholar
  22. 22.
    Yankaskas, J.R., Gatzy, J.T., Knowles, M.R., Boucher, R.C., 1985, Persistence of abnormal chloride ion permeability in cystic fibrosis nasal epithelial cells in heterologous culture, Lancet, 8435:954.CrossRefGoogle Scholar
  23. 23.
    Jetten, A.M., Yankaskas, J.R., Stutts, M.J., 1989, Persistence of abnormal chloride conductance regulation in transformed cystic fibrosis epithelia, Science 244.1472.PubMedCrossRefGoogle Scholar
  24. 24.
    Cotton, C.U., Stutts, M.J., Knowles, M.R., 1987, Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. An in vitro electrophysiological analysis, J. Clin. Invest., 79:30.CrossRefGoogle Scholar
  25. 25.
    Frizzell, R.A., Rechkemmer, G., Shoemaker, R.L., 1986, Altered regulation of airway epithelial cell chloride channels in cystic fibrosis, Science, 233:558.PubMedCrossRefGoogle Scholar
  26. 26.
    Shoemaker, R.L., Frizzell, R.A., Dwyer, T.M., Farley, J.M., 1986, Single chloride channel currents from canine tracheal epithelial cells, Biochim. Biophys. Acta, 858:235.PubMedCrossRefGoogle Scholar
  27. 27.
    Welsh, M.J., 1986, An apical-membrane chloride channel in human tracheal epithelium, Science, 232:1648.PubMedCrossRefGoogle Scholar
  28. 28.
    Welsh, M. J., 1986, Single apical membrane anion channels in primary cultures of canine tracheal epithelium, Pfluegers Arch., 407:S116.CrossRefGoogle Scholar
  29. 29.
    Duszyk, M., French, A.S., Paul Man, S.F., 1989, The 20-pS chloride channel of the human airway epithelium, Biophys. J., 57:223.CrossRefGoogle Scholar
  30. 30.
    Halm, D.R., Rechkemmer, G.R., Schoumacher, R.A., Frizzell, R.A., 1988, Apical membrane chloride channels in a colonic cell line activated by secretory agonists, Am. J. Physiol., 254:CSOS.Google Scholar
  31. 31.
    Hayslett, J.P., Goegelein, H., Kunzelmarm, K., Greger, R., 1987: Characteristics of apical chloride channels in human colon cells (H19), Pfluegers Arch., 410:487.CrossRefGoogle Scholar
  32. 32.
    Krouse, M.E., Hagiwara, G., Chen, J., 1989, Ion channels in normal human and cystic fibrosis sweat gland cells, Am. J. Physiol., 257: C129.PubMedGoogle Scholar
  33. 33.
    McCann, J.D., Li, M., Welsh, M.J., 1989, Identification and regulation of whole-cell chloride currents in airway epithelium, J. Gen. Physiol., 94:1015.PubMedCrossRefGoogle Scholar
  34. 34.
    Welsh, M.J., Liedtke, C.M., 1986, Chloride and potassium channels in cystic fibrosis airway epithelia, Nature, 322:467.PubMedCrossRefGoogle Scholar
  35. 35.
    Li, M., McCann, J.D., Liedtke, C.M., 1988, Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium, Nature, 3 31:358.CrossRefGoogle Scholar
  36. 36.
    Schoumacher, R.A., Shoemaker, R.L. Halm, D.R., 1987, Phosphorylation fails to activate chloride channels from cystic fibrosis airway cells, Nature, 330:752.PubMedCrossRefGoogle Scholar
  37. 37.
    Hwang, T.C., Lu, L., Zeitlin, P., 1989, Cl-channels in CF: lack of activation by protein kinase C and cAMP-dependent protein kinase, Science, 244:1352.CrossRefGoogle Scholar
  38. 38.
    Walsh, P.A., Ashby, C.D., Gonzalez, C, 1985, Purification and characterization of a protein kinase inhibitor of adenosine 3’,5’-monophosphate-dependent protein kinase, J. Biol. Chem., 246:1977.Google Scholar
  39. 39.
    Li, M., McCann, J.D., Anderson, M.P., 1989, Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia, Science, 244:1353.PubMedCrossRefGoogle Scholar
  40. 40.
    Tamaoki, T., Nomoto, H., Takahashi, I., 1986, Staurosporine, a potent inhibitor of phospholipid/Ca++ dependent protein kinase, Biochem. Biophys. Res. Commun., 135:397.PubMedCrossRefGoogle Scholar
  41. 41.
    Nishizuka, Y., 1984, : The role of protein kinase C in cell surface signal transduction and tumor promotion, Nature, 308:693.PubMedCrossRefGoogle Scholar
  42. 42.
    Nishizuka, Y., 1988, The molecular heterogeneity of protein kinase C and its implications for cellular regulation, Nature, 334:661.PubMedCrossRefGoogle Scholar
  43. 43.
    Hwang, T.C., 1990, Ph.D. thesis: Regulation of epithelial Cl-channels: roles of protein kinases and arachidonic acid. The Johns Hopkins University, School of Medicine.Google Scholar
  44. 44.
    Hockberger, P., Toselli, M., Swandulla, D., Lux, H.D., 1989, A diacylglycerol analogue reduces neuronal calcium currents independently of protein kinase C activation, Nature, 338:340.PubMedCrossRefGoogle Scholar
  45. 45.
    Willumsen, N.J., Boucher, R.C., 1989, Activation of an apical Cl-conductance by Ca2+ ionophores in cystic fibrosis airway epithelia, Am. J. Physiol., 256:C226.PubMedGoogle Scholar
  46. 46.
    Widdicombe, J.H., 1986, Cystic fibrosis and β-adrenergic response of airway epithelial cell culture, Am. J. Physiol., 251:R818.PubMedGoogle Scholar
  47. 47.
    Clancy, J.P., McCann, J.D., Li, M., Welsh, M.J., 1990, Calcium-dependent regulation of airway epithelial chloride channels, Am. J. Physiol., 258:L25.PubMedGoogle Scholar
  48. 48.
    McPhail, L.C., Clayton, C.C., Snyderman, R., 1984, A potential second messenger role for unsaturated fatty acids: activation of Ca2+-dependent protein kinase, Science, 224:622.PubMedCrossRefGoogle Scholar
  49. 49.
    Williams, J.H., Errington, M.L., Lynch, M.A., 1989, Arachidonic acid induces a longterm activity-dependent enhancement of synaptic transmission in the hippocampus, Nature, 341:739.PubMedCrossRefGoogle Scholar
  50. 50.
    Barbour, B., Szatkowski, M., Ingledew, N., Attwell, D., 1989, Arachidonic acid induces a prolonged inhibition of glutamate uptake in glial cells, Nature, 342:918.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim, D., Clapham, D.E., 1989, Potassium channels in cardiac cells activated by arachidonic acid and phospholipids, Science, 244:1174.PubMedCrossRefGoogle Scholar
  52. 52.
    Ordway, R.W., Walsh, J.V., Singer, J.J. Jr., 1989, Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells, Science, 244:1176.PubMedCrossRefGoogle Scholar
  53. 53.
    Sarkadi, B., Cheung, R., Mack, E., 1985, Cation and anion transport pathways in volume regulatory response of human lymphocytes to hyposmotic media, Am. J. Physiol., 248:C480.PubMedGoogle Scholar
  54. 54.
    Landry, D.W., Reitman, M., Cragoe, E.J. Jr., Al-Awqati, Q., 1987, Epithelial chloride channel: Development of inhibitory ligands, J. Gen. Physiol., 90:779.PubMedCrossRefGoogle Scholar
  55. Hwang, T.C., Guggino, S.E., Guggino, W.B., Direct modulation of secretory Cl-channels by arachidonic acid, Accepted for publication by Proc. Natl. Acad. Sci. USA.Google Scholar
  56. 56.
    Dharmsathaphorn, K., McRoberts, J.A., Mandei, K.G., 1984, A human colonic tumor cell line that maintains vectorial electrolyte transport, Am. J. Physiol., 246:G204.PubMedGoogle Scholar
  57. 57.
    Dahlen, S.-E., Hansson, G., Hedqvist, P., 1983, Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotriene C4, D4 and E4, Proc. Natl. Acad. Sci. USA, 80:1712.PubMedCrossRefGoogle Scholar
  58. 58.
    Weiss, J.W., Drazen, J.M., Coles, N., 1982, Bronchoconstrictor effects of leukotriene C in humans, Science, 216:196.PubMedCrossRefGoogle Scholar
  59. 59.
    Hardy, C.C., Robinson, C., Tattersfield, A.E., Holgate, S.T., 1984, The bronchosonstrictor effect of inhales prostaglandin D2 in normal and asthmatic men, N. Engl. J. Med., 311:209.PubMedCrossRefGoogle Scholar
  60. 60.
    Carlstedt-Duke, J., Broennegard, M., Strandvik, B., 1986, Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect, Proc. Natl. Acad. Sci. USA, 83:9202.PubMedCrossRefGoogle Scholar
  61. 61.
    Lewis, R.A., Soter, N.A., Diamond, P.T., 1982, Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immun., 129:1627.PubMedGoogle Scholar
  62. 61.
    Churchill, L., Chilton, F.H., Resau, J.H., 1989, Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells, Am. Rev. Respir. dis., 140:449.PubMedCrossRefGoogle Scholar
  63. 63.
    MacDermot, J., Barnes, P.J., 1980, Activation of guinea pig pulmonary adenylate cyclase by prostacyclin, Eur. J., Pharmacol., 67:419.CrossRefGoogle Scholar
  64. 64.
    Hille, B., 1984, Ionic Channels in Excitable Membranes, Sinauer Association Inc., Massachusetts.Google Scholar
  65. 65.
    White, M.M., Miller, C., 1981, Probes of the conduction process of a voltage-gated Cl-channel from Torpedo electro-plax, J. Gen. Physiol., 78:1.PubMedCrossRefGoogle Scholar
  66. 66.
    Bahinski, A., Nairn, A.C., Greengard, P., Gadsby, D.C., 1989, Chloride conductance regulated by cyclic AMP-dependent protein kinase in cardiac myocytes, Nature, 340:718.PubMedCrossRefGoogle Scholar
  67. 67.
    Levitan I.B., 1988, Modulation of ion channels in neurons and other cells, Ann. Rev. Neurosci., 11:119PubMedCrossRefGoogle Scholar
  68. 68.
    Bean, B.P., Nowycky, M.C., Tsien, R.W., 1984, β-adrenergic modulation of calcium channels in frog ventricular heart cells, Nature 307:371.PubMedCrossRefGoogle Scholar
  69. 69.
    Cachelin, A.B., de Peyer, J.E., Kokubun, S., Reuter, H., 1983, Ca2+ channel modulation by 8-bromocyclic AMP in cultured heart cells, Nature, 304:462.PubMedCrossRefGoogle Scholar
  70. 70.
    Soliven, B., Szuchet, S., Arnason, B.G.W., Nelson, D.J., 1988, Forskolin and phorbol esters decrease the same K+ conductance in cultured oligodendrocytes, J. Membr. Biol., 105:177.PubMedCrossRefGoogle Scholar
  71. 71.
    Sims, S.M., Singer, J.J., Walsh, J.V. Jr., 1988, Antagonistic adrenergic-muscarinic regulation of M current in smooth muscle cells, Science, 239:190.PubMedCrossRefGoogle Scholar
  72. 72.
    Kume, H., Takai, A., Tokuno, H., Tomita, T., 1989, Regulation of Ca2+-dependent K+ channel activity in tracheal myocytes by phosphorylation, Nature, 341:152.PubMedCrossRefGoogle Scholar
  73. 73.
    Nastainczyk, W., Roehrkasten, A., Sieber, M., 1987, Phosphorylation of the purified receptor for calcium channel blockers by cAMP kinase and protein kinase C, Euro. J. Biochem., 169:137.CrossRefGoogle Scholar
  74. Huganir, R.L., Greengard, P., cAMP-dependent protein kinase phosphorylates the nicotinic acetylcholine receptor, Proc. Natl. Acad. Sci. USA, 80:1130.Google Scholar
  75. 75.
    Miles, K., Anthony, D.T., Ruben, L.L., 1987, Regulation of nicotinic acetylcholine receptor phosphorylation in rat myotubes by forskolin and cAMP, Proc. Natl. Acad. Sci. USA, 84:6591.PubMedCrossRefGoogle Scholar
  76. 76.
    Walsh, K.B., Kass, R.S., 1988, Regulation of a heart potassium channel by protein kinase A and C, Science, 242:67.PubMedCrossRefGoogle Scholar
  77. 77.
    Hammond, C., Paupardin-Tritsch, D., Nairn, A.C., 1987, Cholecystokinin induces a decrease in Ca2+ current in snail neurons that appears to be mediated by protein kinase C, Nature, 325:809.PubMedCrossRefGoogle Scholar
  78. 78.
    Lacerda, A.E., Rampe, D., Brown, A.M., 1988, Effects of protein kinase C activators on cardiac Ca2+ channels, Nature, 335:249.PubMedCrossRefGoogle Scholar
  79. 79.
    Strong, J.A., Fox, A.P., Tsien, R.W., Kaczmarek, L.K., 1987 Stimulation of protein kinase C recruits covert calcium channels in Aplysia bag cell neurons, Nature, 325:714.PubMedCrossRefGoogle Scholar
  80. 80.
    Miles, K., Huganir, R.L., 1988, Regulation of nicotinic acetylcholine receptors by protein phosphorylation, Mol. Neuro-biol. 2:91.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Tzyh-Chang Hwang
    • 1
  • William B. Guggino
    • 1
  1. 1.Department of Physiology, School of MedicineThe Johns Hopkins UniversityUSA

Personalised recommendations