Roles of Corneal Epithelial Ion Transport Mechanisms in Mediating Responses to Cytokines and Osmotic Stress

  • Peter S. Reinach
  • José E. Capó-Aponte
  • Stefan Mergler
  • Kathryn S. Pokorny
Part of the Ophthalmology Research book series (OPHRES)


Normal vision depends, in part, on the combined refractive powers of the cornea and crystalline lens to permit adequate focusing of light onto the retina. Such refractive function requires that the cornea remain transparent, a requirement that is met provided that corneal hydration, i.e., deturgescence, is maintained within specific physiological limits. Maintenance of corneal deturgescence is reliant upon coupled ion and fluid transport activities within the epithelial and endothelial layers. Net ion transport activity offsets the natural tendency of the corneal stroma to imbibe fluid from the anterior chamber, thus keeping the cornea transparent ( 1, 2, 3, 4, 5). Although most of the ion transport activity involved in maintaining corneal deturgescence is contingent upon ion transport processes localized in the corneal endothelial layer, corneal epithelial ion transport activity plays a fine-tuning role in maintaining corneal deturgescence during exposure to environmental...


Corneal Epithelium Regulatory Volume Decrease Corneal Epithelial Cell Human Corneal Epithelial Cell Regulatory Volume Increase 
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.



This work was support by grants EY04795 (PR) and by an unrestricted grant from Research to Prevent Blindness, Inc., NY (KP).


  1. 1.
    1. Klyce SD. Transport of Na, Cl, and water by the rabbit corneal epithelium at resting potential. Am J Physiol 1975;228:1446–1452.PubMedGoogle Scholar
  2. 2.
    2. Maurice DM. The permeability to sodium ions of the living rabbit's cornea. J Physiol 1951;112:367–391.PubMedGoogle Scholar
  3. 3.
    3. Maurice DM. Influence on corneal permeability of bathing with solutions of differing reaction and tonicity. Br J Ophthalmol 1955;39:463–473.PubMedGoogle Scholar
  4. 4.
    4. Maurice DM. The location of the fluid pump in the cornea. J Physiol 1972;221:43–54.PubMedGoogle Scholar
  5. 5.
    5. Zucker BB. Hydration and transparency of corneal stroma. Arch Ophthalmol 1966;75: 228–231.PubMedGoogle Scholar
  6. 6.
    6. Klyce SD, Wong RK. Site and mode of adrenaline action on chloride transport across the rabbit corneal epithelium. J Physiol 1977;266:777–799.PubMedGoogle Scholar
  7. 7.
    7. Klyce SD. Enhancing fluid secretion by the corneal epithelium. Invest Ophthalmol Vis Sci 1977;16:968–973.PubMedGoogle Scholar
  8. 8.
    8. Li HF, Petroll WM, Moller-Pedersen T, Maurer JK, Cavanagh HD, Jester JV. Epithelial and corneal thickness measurements by in vivo confocal microscopy through focusing (CMTF). Curr Eye Res 1997;16:214–221.PubMedGoogle Scholar
  9. 9.
    9. Jakus M. The fine structure of the hyman cornea. In: Smelser G, ed. The structure of the eye. New York: Academia, 1969:344.Google Scholar
  10. 10.
    10. Baum JP, Maurice DM, McCarey BE. The active and passive transport of water across the corneal endothelium. Exp Eye Res 1984;39:335–342.PubMedGoogle Scholar
  11. 11.
    11. Zadunaisky JA, Lande MA, Chalfie M, Neufeld AH. Ion pumps in the cornea and their stimulation by epinephrine and cyclic-AMP. Exp Eye Res 1973;15:577–584.PubMedGoogle Scholar
  12. 12.
    12. Klyce SD, Palkama KA, Harkonen M, Marshall WS, Huhtaniitty S, Mann KP, Neufeld AH. Neural serotonin stimulates chloride transport in the rabbit corneal epithelium. Invest Ophthalmol Vis Sci 1982;23:181–192.PubMedGoogle Scholar
  13. 13.
    13. Pesin SR, Candia OA. Acetylcholine concentration and its role in ionic transport by the corneal epithelium. Invest Ophthalmol Vis Sci 1982;22:651–659.PubMedGoogle Scholar
  14. 14.
    14. Candia OA, Podos SM, Neufeld AH. Modification by timolol of catecholamine stimulation of chloride transport in isolated corneas. Invest Ophthalmol Vis Sci 1979;18:691–695.PubMedGoogle Scholar
  15. 15.
    15. Chu TC, Candia OA. Role of alpha 1- and alpha 2-adrenergic receptors in Cl- transport across frog corneal epithelium. Am J Physiol 1988;255:C724–730.PubMedGoogle Scholar
  16. 16.
    16. Montoreano R, Candia OA, Cook P. alpha- and beta-adrenergic receptors in regulation of ionic transport in frog cornea. Am J Physiol 1976;230:1487–1493.PubMedGoogle Scholar
  17. 17.
    17. Cavanagh HD, Colley AM. Cholinergic, adrenergic, and PGE1 effects on cyclic nucleotides and growth in cultured corneal epithelium. Metab Pediatr Syst Ophthalmol 1982;6:63–74.PubMedGoogle Scholar
  18. 18.
    18. Lu L, Reinach PS, Kao WW. Corneal epithelial wound healing. Exp Biol Med (Maywood) 2001;226:653–664.Google Scholar
  19. 19.
    19. Yang H, Wang Z, Miyamoto Y, Reinach PS. Cell signaling pathways mediating epidermal growth factor stimulation of Na:K:2Cl cotransport activity in rabbit corneal epithelial cells. J Membr Biol 2001;183:93–101.PubMedGoogle Scholar
  20. 20.
    20. Roderick C, Reinach PS, Wang L, Lu L. Modulation of rabbit corneal epithelial cell proliferation by growth factor-regulated K(+) channel activity. J Membr Biol 2003;196:41–50.PubMedGoogle Scholar
  21. 21.
    21. Candia OA, Grillone LR, Chu TC. Forskolin effects on frog and rabbit corneal epithelium ion transport. Am J Physiol 1986;251:C448–454.PubMedGoogle Scholar
  22. 22.
    22. Candia OA. Ouabain and sodium effects on chloride fluxes across the isolated bullfrog cornea. Am J Physiol 1972;223:1053–1057.PubMedGoogle Scholar
  23. 23.
    23. Wu X, Yang H, Iserovich P, Fischbarg J, Reinach PS. Regulatory volume decrease by SV40-transformed rabbit corneal epithelial cells requires ryanodine-sensitive Ca2+-induced Ca2+ release. J Membr Biol 1997;158:127–136.PubMedGoogle Scholar
  24. 24.
    24. Capo-Aponte JE, Iserovich P, Reinach PS. Characterization of regulatory volume behavior by fluorescence quenching in human corneal epithelial cells. J Membr Biol 2005;207:11–22.PubMedGoogle Scholar
  25. 25.
    25. Farris RL. Tear osmolarity–a new gold standard? Adv Exp Med Biol 1994;350:495–503.PubMedGoogle Scholar
  26. 26.
    26. Bildin VN, Yang H, Fischbarg J, Reinach PS. Effects of chronic hypertonic stress on regulatory volume increase and Na-K-2Cl cotransporter expression in cultured corneal epithelial cells. Adv Exp Med Biol 1998;438:637–642.PubMedGoogle Scholar
  27. 27.
    27. Bildin VN, Wang Z, Iserovich P, Reinach PS. Hypertonicity-induced p38MAPK activation elicits recovery of corneal epithelial cell volume and layer integrity. J Membr Biol 2003;193:1–13.PubMedGoogle Scholar
  28. 28.
    28. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D. Functional significance of cell volume regulatory mechanisms. Physiol Rev 1998;78:247–306.PubMedGoogle Scholar
  29. 29.
    29. Capo-Aponte JE, Wang Z, Bildin VN, Pokorny KS, Reinach PS. Fate of Hypertonicity-Stressed Corneal Epithelial Cells Depends on Differential MAPK Activation and p38MAPK/Na-K-2Cl Cotransporter1 Interaction. Exp Eye Res 2007;84:361–372.PubMedGoogle Scholar
  30. 30.
    30. Saika S, Okada Y, Miyamoto T, Yamanaka O, Ohnishi Y, Ooshima A, Liu CY, Weng D, Kao WW. Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium. Invest Ophthalmol Vis Sci 2004;45:100–109.PubMedGoogle Scholar
  31. 31.
    31. Sharma GD, He J, Bazan HE. p38 and ERK1/2 coordinate cellular migration and proliferation in epithelial wound healing: evidence of cross-talk activation between MAP kinase cascades. J Biol Chem 2003;278:21989–21997.PubMedGoogle Scholar
  32. 32.
    32. Kang SS, Li T, Xu D, Reinach PS, Lu L. Inhibitory effect of PGE2 on EGF-induced MAP kinase activity and rabbit corneal epithelial proliferation. Invest Ophthalmol Vis Sci 2000;41:2164–2169.PubMedGoogle Scholar
  33. 33.
    33. Kang SS, Wang L, Kao WW, Reinach PS, Lu L. Control of SV-40 transformed RCE cell proliferation by growth-factor-induced cell cycle progression. Curr Eye Res 2001;23:397–405.PubMedGoogle Scholar
  34. 34.
    34. Wang Z, Yang H, Tachado SD, Capo-Aponte JE, Bildin VN, Koziel H, Reinach PS. Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 2006;47:5267–5275.PubMedGoogle Scholar
  35. 35.
    35. Lu L. Stress-induced corneal epithelial apoptosis mediated by K(+) channel activation. Prog Retin Eye Res 2006;25:515–538.PubMedGoogle Scholar
  36. 36.
    36. Zadunaisky JA, Lande MA. Active chloride transport and control of corneal transparency. Am J Physiol 1971;221:1837–1844.PubMedGoogle Scholar
  37. 37.
    37. Candia OA, Reinach PS, Alvarez L. Amphotericin B-induced active transport of K+ and the Na+-K+ flux ratio in frog corneal epithelium. Am J Physiol 1984;247:C454–461.PubMedGoogle Scholar
  38. 38.
    38. Davson H. The influence of the lyotropic series of anions on cation permeability. Biochem J 1940;34:917–925.PubMedGoogle Scholar
  39. 39.
    39. Ljubimov AV, Atilano SR, Garner MH, Maguen E, Nesburn AB, Kenney MC. Extracellular matrix and Na+,K+-ATPase in human corneas following cataract surgery: comparison with bullous keratopathy and Fuchs’ dystrophy corneas. Cornea 2002;21:74–80.PubMedGoogle Scholar
  40. 40.
    40. Cejkova J, Lojda Z, Brunova B, Vacik J, Michalek J. Disturbances in the rabbit cornea after short-term and long-term wear of hydrogel contact lenses. Usefulness of histochemical methods. Histochemistry 1988;89:91–97.PubMedGoogle Scholar
  41. 41.
    41. Conners MS, Urbano F, Vafeas C, Stoltz RA, Dunn MW, Schwartzman ML. Alkali burn-induced synthesis of inflammatory eicosanoids in rabbit corneal epithelium. Invest Ophthalmol Vis Sci 1997;38:1963–1971.PubMedGoogle Scholar
  42. 42.
    42. Masferrer JL, Rios AP, Schwartzman ML. Inhibition of renal, cardiac and corneal (Na(+)-K+)ATPase by 12(R)-hydroxyeicosatetraenoic acid. Biochem Pharmacol 1990;39:1971–1974.PubMedGoogle Scholar
  43. 43.
    43. Schwartzman ML, Balazy M, Masferrer J, Abraham NG, McGiff JC, Murphy RC. 12(R)-hydroxyicosatetraenoic acid: a cytochrome-P450-dependent arachidonate metabolite that inhibits Na+,K+-ATPase in the cornea. Proc Natl Acad Sci USA 1987;84:8125–8129.PubMedGoogle Scholar
  44. 44.
    44. Vafeas C, Mieyal PA, Urbano F, Falck JR, Chauhan K, Berman M, Schwartzman ML. Hypoxia stimulates the synthesis of cytochrome P450-derived inflammatory eicosanoids in rabbit corneal epithelium. J Pharmacol Exp Ther 1998;287:903–910.PubMedGoogle Scholar
  45. 45.
    45. Ottino P TF, Bazan HE. Growth factor-induced proliferation in corneal epithelial cells is mediated by 12(S)-HETE. Exp Eye Res 2003;76:613–622.PubMedGoogle Scholar
  46. 46.
    46. Bildin VN, Yang H, Crook RB, Fischbarg J, Reinach PS. Adaptation by corneal epithelial cells to chronic hypertonic stress depends on upregulation of Na:K:2Cl cotransporter gene and protein expression and ion transport activity. J Membr Biol 2000;177:41–50.PubMedGoogle Scholar
  47. 47.
    47. Al-Nakkash L, Iserovich P, Coca-Prados M, Yang H, Reinach PS. Functional and molecular characterization of a volume-activated chloride channel in rabbit corneal epithelial cells. J Membr Biol 2004;201:41–49.PubMedGoogle Scholar
  48. 48.
    48. Wehner F, Olsen H, Tinel H, Kinne-Saffran E, Kinne RK. Cell volume regulation: osmolytes, osmolyte transport, and signal transduction. Rev Physiol Biochem Pharmacol 2003;148:1–80.PubMedGoogle Scholar
  49. 49.
    49. Jakab M, Ritter M. Cell volume regulatory ion transport in the regulation of cell migration. Contrib Nephrol 2006;152:161–180.PubMedGoogle Scholar
  50. 50.
    50. Gobbels M, Spitznas M. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. Ophthalmology 1992;99:873–878.PubMedGoogle Scholar
  51. 51.
    51. Fleiszig SM, Zaidi TS, Pier GB. Mucus and Pseudomonas aeruginosa adherence to the cornea. Adv Exp Med Biol 1994;350:359–362.PubMedGoogle Scholar
  52. 52.
    52. Xu KP, Yagi Y, Tsubota K. Decrease in corneal sensitivity and change in tear function in dry eye. Cornea 1996;15:235–239.PubMedGoogle Scholar
  53. 53.
    53. Imanishi J, Kamiyama K, Iguchi I, Kita M, Sotozono C, Kinoshita S. Growth factors: importance in wound healing and maintenance of transparency of the cornea. Prog Retin Eye Res 2000;19:113–129.PubMedGoogle Scholar
  54. 54.
    54. Bildin VN, Iserovich P, Fischbarg J, Reinach PS. Differential expression of Na:K:2Cl cotransporter, glucose transporter 1, and aquaporin 1 in freshly isolated and cultured bovine corneal tissues. Exp Biol Med (Maywood) 2001;226:919–926.Google Scholar
  55. 55.
    55. Bortner CD, Cidlowski JA. Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am J Physiol 1996;271:C950–961.PubMedGoogle Scholar
  56. 56.
    56. Wilson SE, Mohan RR, Hong J, Lee J, Choi R, Liu JJ. Apoptosis in the cornea in response to epithelial injury: significance to wound healing and dry eye. Adv Exp Med Biol 2002;506:821–826.PubMedGoogle Scholar
  57. 57.
    57. Capo-Aponte JE, Wang Z, Bildin VN, Iserovich P, Pan Z, Zhang F, Pokorny KS, Reinach PS. Functional and molecular characterization of multiple K-Cl cotransporter isoforms in corneal epithelial cells. Exp Eye Res 2007;84:1090–1103.PubMedGoogle Scholar
  58. 58.
    58. Shen MR, Chou CY, Hsu KF, Liu HS, Dunham PB, Holtzman EJ, Ellory JC. The KCl cotransporter isoform KCC3 can play an important role in cell growth regulation. Proc Natl Acad Sci USA 2001;98:14714–14719.PubMedGoogle Scholar
  59. 59.
    59. Shen MR, Chou CY, Hsu KF, Hsu YM, Chiu WT, Tang MJ, Alper SL, Ellory JC. KCl cotransport is an important modulator of human cervical cancer growth and invasion. J Biol Chem 2003;278:39941–39950.PubMedGoogle Scholar
  60. 60.
    60. Shen MR, Lin AC, Hsu YM, Chang TJ, Tang MJ, Alper SL, Ellory JC, Chou CY. Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells. J Biol Chem 2004;279:40017–40025.PubMedGoogle Scholar
  61. 61.
    61. Bonanno JA, Polse KA. Corneal acidosis during contact lens wear: effects of hypoxia and CO2. Invest Ophthalmol Vis Sci 1987;28:1514–1520.PubMedGoogle Scholar
  62. 62.
    62. Korbmacher C, Helbig H, Forster C, Wiederholt M. Evidence for Na+/H+ exchange and pH sensitive membrane voltage in cultured bovine corneal epithelial cells. Curr Eye Res 1988;7:619–626.PubMedGoogle Scholar
  63. 63.
    63. Korbmacher C, Helbig H, Forster C, Wiederholt M. Characterization of Na+/H+ exchange in a rabbit corneal epithelial cell line (SIRC). Biochim Biophys Acta 1988;943:405–410.PubMedGoogle Scholar
  64. 64.
    64. Bonanno JA. K(+)-H+ exchange, a fundamental cell acidifier in corneal epithelium. Am J Physiol 1991;260:C618–625.PubMedGoogle Scholar
  65. 65.
    65. Shepard AR, Rae JL. Ion transporters and receptors in cDNA libraries from lens and cornea epithelia. Curr Eye Res 1998;17:708–719.PubMedGoogle Scholar
  66. 66.
    66. Wu X, Torres-zamorano V, Yang H, Reinach PS. ETA receptor mediated inhibition of intracellular pH regulation in cultured bovine corneal epithelial cells. Exp Eye Res 1998;66:699–708.PubMedGoogle Scholar
  67. 67.
    67. Reinach P, Ganapathy V, Torres-Zamorano V. A Na:H exchanger subtype mediates volume regulation in bovine corneal epithelial cells. Adv Exp Med Biol 1994;350:105–110.PubMedGoogle Scholar
  68. 68.
    68. Takagi H, Reinach PS, Tachado SD, Yoshimura N. Endothelin-mediated cell signaling and proliferation in cultured rabbit corneal epithelial cells. Invest Ophthalmol Vis Sci 1994;35:134–142.PubMedGoogle Scholar
  69. 69.
    69. Takagi H, Reinach PS, Yoshimura N, Honda Y. Endothelin-1 promotes corneal epithelial wound healing in rabbits. Curr Eye Res 1994;13:625–628.PubMedGoogle Scholar
  70. 70.
    70. Tao W, Liou GI, Wu X, Abney TO, Reinach PS. ETB and epidermal growth factor receptor stimulation of wound closure in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 1995;36:2614–2622.PubMedGoogle Scholar
  71. 71.
    71. Fischbarg J, Hernandez J, Liebovitch LS, Koniarek JP. The mechanism of fluid and electrolyte transport across corneal endothelium: critical revision and update of a model. Curr Eye Res 1985;4:351–360.PubMedGoogle Scholar
  72. 72.
    72. Bonanno JA. Identity and regulation of ion transport mechanisms in the corneal endothelium. Prog Retin Eye Res 2003;22:69–94.PubMedGoogle Scholar
  73. 73.
    73. Candia OA, Montoreano R, Podos SM. Effect of the ionophore A23187 on chloride transport across isolated frog cornea. Am J Physiol 1977;233:F94–101.PubMedGoogle Scholar
  74. 74.
    74. Leiper LJ, Walczysko P, Kucerova R, Ou J, Shanley LJ, Lawson D, Forrester JV, McCaig CD, Zhao M, Collinson JM. The roles of calcium signaling and ERK1/2 phosphorylation in a Pax6+/- mouse model of epithelial wound-healing delay. BMC Biol 2006;4:27.PubMedGoogle Scholar
  75. 75.
    75. Yang H, Sun X, Wang Z, Ning G, Zhang F, Kong J, Lu L, Reinach PS. EGF stimulates growth by enhancing capacitative calcium entry in corneal epithelial cells. J Membr Biol 2003;194:47–58.PubMedGoogle Scholar
  76. 76.
    76. Reinach P, Holmberg N. Ca-stimulated Mg dependent ATPase activity in a plasma membrane enriched fraction of bovine corneal epithelium. Curr Eye Res 1987;6:399–405.PubMedGoogle Scholar
  77. 77.
    77. Reinach PS, Holmberg N, Chiesa R. Identification of calmodulin-sensitive Ca(2+)-transporting ATPase in the plasma membrane of bovine corneal epithelial cell. Biochim Biophys Acta 1991;1068:1–8.PubMedGoogle Scholar
  78. 78.
    78. Verma AK, Filoteo AG, Stanford DR, Wieben ED, Penniston JT, Strehler EE, Fischer R, Heim R, Vogel G, Mathews S, et al. Complete primary structure of a human plasma membrane Ca2+ pump. J Biol Chem 1988;263:14152–14159.PubMedGoogle Scholar
  79. 79.
    79. Johnson JA, Grande JP, Roche PC, Campbell RJ, Kumar R. Immuno-localization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye. Curr Eye Res 1995;14:101–108.PubMedGoogle Scholar
  80. 80.
    80. Talarico EF, Jr., Kennedy BG, Marfurt CF, Loeffler KU, Mangini NJ. Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium. Mol Vis 2005;11:169–178.PubMedGoogle Scholar
  81. 81.
    81. Rich A, Rae JL. Calcium entry in rabbit corneal epithelial cells: evidence for a nonvoltage dependent pathway. J Membr Biol 1995;144:177–184.PubMedGoogle Scholar
  82. 82.
    82. Tao W, Wu X, Liou GI, Abney TO, Reinach PS. Endothelin receptor-mediated Ca2+ signaling and isoform expression in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 1997;38:130–141.PubMedGoogle Scholar
  83. 83.
    83. Socci RR, Tachado SD, Aronstam RS, Reinach PS. Characterization of the muscarinic receptor subtypes in the bovine corneal epithelial cells. J Ocul Pharmacol Ther 1996;12:259–269.PubMedGoogle Scholar
  84. 84.
    84. Yang H, Mergler S, Sun X, Wang Z, Lu L, Bonanno JA, Pleyer U, Reinach PS. TRPC4 knockdown suppresses epidermal growth factor-induced store-operated channel activation and growth in human corneal epithelial cells. J Biol Chem 2005;280:32230–32237.PubMedGoogle Scholar
  85. 85.
    85. Zhang F, Wen Q, Mergler S, Yang H, Wang Z, Bildin VN, Reinach PS. PKC isoform-specific enhancement of capacitative calcium entry in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2006;47:3989–4000.PubMedGoogle Scholar
  86. 86.
    86. Bonanno JA. Lactate-proton cotransport in rabbit corneal epithelium. Curr Eye Res 1990;9:707–712.PubMedGoogle Scholar
  87. 87.
    87. Klyce SD. Stromal lactate accumulation can account for corneal oedema osmotically following epithelial hypoxia in the rabbit. J Physiol 1981;321:49–64.PubMedGoogle Scholar
  88. 88.
    88. Lambert SR, Klyce SD. The origins of Sattler's veil. Am J Ophthalmol 1981;91:51–56.PubMedGoogle Scholar
  89. 89.
    89. Kumagai AK, Glasgow BJ, Pardridge WM. GLUT1 glucose transporter expression in the diabetic and nondiabetic human eye. Invest Ophthalmol Vis Sci 1994;35:2887–2894.PubMedGoogle Scholar
  90. 90.
    90. Takahashi H, Kaminski AE, Zieske JD. Glucose transporter 1 expression is enhanced during corneal epithelial wound repair. Exp Eye Res 1996;63:649–659.PubMedGoogle Scholar
  91. 91.
    91. Loike JD, Cao L, Kuang K, Vera JC, Silverstein SC, Fischbarg J. Role of facilitative glucose transporters in diffusional water permeability through J774 cells. J Gen Physiol 1993;102:897–906.PubMedGoogle Scholar
  92. 92.
    92. Ito A, Yamaguchi K, Tomita H, Suzuki T, Onogawa T, Sato T, Mizutamari H, Mikkaichi T, Nishio T, Unno M, Sasano H, Abe T, Tamai M. Distribution of rat organic anion transporting polypeptide-E (oatp-E) in the rat eye. Invest Ophthalmol Vis Sci 2003;44:4877–4884.PubMedGoogle Scholar
  93. 93.
    93. Coulombre AJ, Coulombre JL. Corneal Development. 3. The Role of the Thyroid in Dehydration and the Development of Transparency. Exp Eye Res 1964;75:105–114.Google Scholar
  94. 94.
    94. Jain-Vakkalagadda B, Dey S, Pal D, Mitra AK. Identification and functional characterization of a Na+-independent large neutral amino acid transporter, LAT1, in human and rabbit cornea. Invest Ophthalmol Vis Sci 2003;44:2919–2927.PubMedGoogle Scholar
  95. 95.
    95. Jain-Vakkalagadda B, Pal D, Gunda S, Nashed Y, Ganapathy V, Mitra AK. Identification of a Na+-dependent cationic and neutral amino acid transporter, B(0,+), in human and rabbit cornea. Mol Pharm 2004;1:338–346.PubMedGoogle Scholar
  96. 96.
    96. Katragadda S, Talluri RS, Pal D, Mitra AK. Identification and characterization of a Na+-dependent neutral amino acid transporter, ASCT1, in rabbit corneal epithelial cell culture and rabbit cornea. Curr Eye Res 2005;30:989–1002.PubMedGoogle Scholar
  97. 97.
    97. Takami Y, Gong H, Amemiya T. Riboflavin deficiency induces ocular surface damage. Ophthalmic Res 2004;36:156–165.PubMedGoogle Scholar
  98. 98.
    98. Stern JJ. The ocular manifestations of riboflavin deficiency. Am J Ophthalmol 1950;33:1127–1136.PubMedGoogle Scholar
  99. 99.
    99. Jackson CR. Riboflavin deficiency with ocular signs: report of a case. Br J Ophthalmol 1950;34: 259–260.PubMedGoogle Scholar
  100. 100.
    100. Hariharan S, Janoria KG, Gunda S, Zhu X, Pal D, Mitra AK. Identification and functional expression of a carrier-mediated riboflavin transport system on rabbit corneal epithelium. Curr Eye Res 2006;31:811–824.PubMedGoogle Scholar
  101. 101.
    101. Ringvold A, Anderssen E, Kjonniksen I. Impact of the environment on the mammalian corneal epithelium. Invest Ophthalmol Vis Sci 2003;44:10–15.PubMedGoogle Scholar
  102. 102.
    102. Choy CK, Benzie IF, Cho P. Is ascorbate in human tears from corneal leakage or from lacrimal secretion? Clin Exp Optom 2004;87:24–27.PubMedGoogle Scholar
  103. 103.
    103. Brubaker RF, Bourne WM, Bachman LA, McLaren JW. Ascorbic acid content of human corneal epithelium. Invest Ophthalmol Vis Sci 2000;41:1681–1683.PubMedGoogle Scholar
  104. 104.
    104. Williams RN, Paterson CA. Modulation of corneal lipoxygenase by ascorbic acid. Exp Eye Res 1986;43:7–13.PubMedGoogle Scholar
  105. 105.
    105. Shimmura S, Masumizu T, Nakai Y, Urayama K, Shimazaki J, Bissen-Miyajima H, Kohno M, Tsubota K. Excimer laser-induced hydroxyl radical formation and keratocyte death in vitro. Invest Ophthalmol Vis Sci 1999;40:1245–1249.PubMedGoogle Scholar
  106. 106.
    106. Tsukaguchi H, Tokui T, Mackenzie B, Berger UV, Chen XZ, Wang Y, Brubaker RF, Hediger MA. A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature 1999;399:70–75.PubMedGoogle Scholar
  107. 107.
    107. Talluri RS, Katragadda S, Pal D, Mitra AK. Mechanism of L-ascorbic acid uptake by rabbit corneal epithelial cells: evidence for the involvement of sodium-dependent vitamin C transporter 2. Curr Eye Res 2006;31:481–489.PubMedGoogle Scholar
  108. 108.
    108. Janoria KG, Hariharan S, Paturi D, Pal D, Mitra AK. Biotin uptake by rabbit corneal epithelial cells: role of sodium-dependent multivitamin transporter (SMVT). Curr Eye Res 2006;31:797–809.PubMedGoogle Scholar
  109. 109.
    109. Shioda R, Reinach PS, Hisatsune T, Miyamoto Y. Osmosensitive taurine transporter expression and activity in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2002;43:2916–2922.PubMedGoogle Scholar
  110. 110.
    110. Nilius B, Voets T. TRP channels: a TR(I)P through a world of multifunctional cation channels. Pflugers Arch 2005;451:1–10.PubMedGoogle Scholar
  111. 111.
    111. Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA. International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev 2005;57:509–526.PubMedGoogle Scholar
  112. 112.
    112. Goldstein SA, Wang KW, Ilan N, Pausch MH. Sequence and function of the two P domain potassium channels: implications of an emerging superfamily. J Mol Med 1998;76:13–20.PubMedGoogle Scholar
  113. 113.
    113. Chandy KG, Gutman GA. Nomenclature for mammalian potassium channel genes. Trends Pharmacol Sci 1993;14:434.PubMedGoogle Scholar
  114. 114.
    114. Desir G. Molecular physiology of renal potassium channels. Semin Nephrol 1992;12: 531–540.PubMedGoogle Scholar
  115. 115.
    115. Faber ES, Sah P. Calcium-activated potassium channels: multiple contributions to neuronal function. Neuroscientist 2003;9:181–194.PubMedGoogle Scholar
  116. 116.
    116. Giebisch G. Renal potassium channels: function, regulation, and structure. Kidney Int 2001;60:436–445.PubMedGoogle Scholar
  117. 117.
    117. Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity and regulation of renal potassium channels. Physiol Rev 2005;85:319–371.PubMedGoogle Scholar
  118. 118.
    118. Korn SJ, Trapani JG. Potassium channels. IEEE Trans Nanobiosci 2005;4:21–33.Google Scholar
  119. 119.
    119. MacKinnon R. Potassium channels. FEBS Lett 2003;555:62–65.PubMedGoogle Scholar
  120. 120.
    120. Wolosin JM, Candia OA. Cl- secretagogues increase basolateral K+ conductance of frog corneal epithelium. Am J Physiol 1987;253:C555–560.PubMedGoogle Scholar
  121. 121.
    121. Farrugia G, Rae JL. Regulation of a potassium-selective current in rabbit corneal epithelium by cyclic GMP, carbachol and diltiazem. J Membr Biol 1992;129:99–107.PubMedGoogle Scholar
  122. 122.
    122. Bockman CS, Griffith M, Watsky MA. Properties of whole-cell ionic currents in cultured human corneal epithelial cells. Invest Ophthalmol Vis Sci 1998;39:1143–1151.PubMedGoogle Scholar
  123. 123.
    123. Takahira M, Sakurada N, Segawa Y, Shirao Y. Two types of K+ currents modulated by arachidonic acid in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 2001;42:1847–1854.PubMedGoogle Scholar
  124. 124.
    124. Watsky MA, Cooper K, Rae JL. Sodium channels in ocular epithelia. Pflugers Arch 1991;419:454–459.PubMedGoogle Scholar
  125. 125.
    125. Nagel W, Reinach P. Mechanism of stimulation by epinephrine of active transepithelial Cl transport in isolated frog cornea. J Membr Biol 1980;56:73–79.PubMedGoogle Scholar
  126. 126.
    126. Yang H, Reinach PS, Koniarek JP, Wang Z, Iserovich P, Fischbarg J. Fluid transport by cultured corneal epithelial cell layers. Br J Ophthalmol 2000;84:199–204.PubMedGoogle Scholar
  127. 127.
    127. Hartzell C, Putzier I, Arreola J. Calcium-activated chloride channels. Annu Rev Physiol 2005;67:719–758.PubMedGoogle Scholar
  128. 128.
    128. Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev 2002;82:503–568.PubMedGoogle Scholar
  129. 129.
    129. Nilius B, Droogmans G. Amazing chloride channels: an overview. Acta Physiol Scand 2003;177: 119–147.PubMedGoogle Scholar
  130. 130.
    130. Pusch M. Structural insights into chloride and proton-mediated gating of CLC chloride channels. Biochemistry 2004;43:1135–1144.PubMedGoogle Scholar
  131. 131.
    131. Marshall WS, Hanrahan JW. Anion channels in the apical membrane of mammalian corneal epithelium primary cultures. Invest Ophthalmol Vis Sci 1991;32:1562–1568.PubMedGoogle Scholar
  132. 132.
    132. Al-Nakkash L, Reinach PS. Activation of a CFTR-mediated chloride current in a rabbit corneal epithelial cell line. Invest Ophthalmol Vis Sci 2001;42:2364–2370.PubMedGoogle Scholar
  133. 133.
    133. 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;57:411–425.PubMedGoogle Scholar
  134. 134.
    134. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 2000;16:521–555.PubMedGoogle Scholar
  135. 135.
    135. McDonald TF, Pelzer S, Trautwein W, Pelzer DJ. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 1994;74:365–507.PubMedGoogle Scholar
  136. 136.
    136. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985;260:3440–3450.PubMedGoogle Scholar
  137. 137.
    137. Du JW, Zhang F, Capo-Aponte JE, Tachado SD, Zhang J, Yu FS, Sack RA, Koziel H, Reinach PS. AsialoGM1-mediated IL-8 release by human corneal epithelial cells requires coexpression of TLR5. Invest Ophthalmol Vis Sci 2006;47:4810–4818.PubMedGoogle Scholar
  138. 138.
    138. Clapham DE. TRP channels as cellular sensors. Nature 2003;426:517–524.PubMedGoogle Scholar
  139. 139.
    139. Clapham DE, Julius D, Montell C, Schultz G. International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacol Rev 2005;57:427–450.PubMedGoogle Scholar
  140. 140.
    140. Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci STKE 2001;2001:re1.PubMedGoogle Scholar
  141. 141.
    141. Montell C. The TRP superfamily of cation channels. Sci STKE 2005;2005:re3.PubMedGoogle Scholar
  142. 142.
    142. Pedersen SF, Owsianik G, Nilius B. TRP channels: an overview. Cell Calcium 2005;38: 233–252.PubMedGoogle Scholar
  143. 143.
    143. Sanchez MG, Sanchez AM, Collado B, Malagarie-Cazenave S, Olea N, Carmena MJ, Prieto JC, Diaz-Laviada II. Expression of the transient receptor potential vanilloid 1 (TRPV1) in LNCaP and PC-3 prostate cancer cells and in human prostate tissue. Eur J Pharmacol 2005;515:20–27.PubMedGoogle Scholar
  144. 144.
    144. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 2004;430:748–754.PubMedGoogle Scholar
  145. 145.
    145. Weil A, Moore SE, Waite NJ, Randall A, Gunthorpe MJ. Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8. Mol Pharmacol 2005;68:518–527.PubMedGoogle Scholar
  146. 146.
    146. Liedtke W. TRPV4 as osmosensor: a transgenic approach. Pflugers Arch 2005;451:176–180.PubMedGoogle Scholar
  147. 147.
    147. Kochukov MY, McNearney TA, Fu Y, Westlund KN. Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes. Am J Physiol Cell Physiol 2006;291:C424–432.PubMedGoogle Scholar
  148. 148.
    148. Zhang L, Jones S, Brody K, Costa M, Brookes SJ. Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am J Physiol Gastrointest Liver Physiol 2004;286:G983–991.PubMedGoogle Scholar
  149. 149.
    149. Mergler S, Pleyer U, Reinach P, Bednarz J, Dannowski H, Engelmann K, Hartmann C, Yousif T. EGF suppresses hydrogen peroxide induced Ca2+ influx by inhibiting L-type channel activity in cultured human corneal endothelial cells. Exp Eye Res 2005;80:285–293.PubMedGoogle Scholar
  150. 150.
    150. Hsu JK, Cavanagh HD, Jester JV, Ma L, Petroll WM. Changes in corneal endothelial apical junctional protein organization after corneal cold storage. Cornea 1999;18:712–720.PubMedGoogle Scholar
  151. 151.
    151. Lindstrom RL. Advances in corneal preservation. Trans Am Ophthalmol Soc 1990;88:555–648.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Peter S. Reinach
    • 1
  • José E. Capó-Aponte
    • 1
  • Stefan Mergler
    • 1
  • Kathryn S. Pokorny
    • 2
  1. 1.Department of Biological SciencesState University of New YorkNew YorkUSA
  2. 2.The Institute of Ophthalmology and Visual ScienceNew Jersey Medical School, University of Medicine and DentistryNewarkNJ

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