Advertisement

Claudins: vital partners in transcellular and paracellular transport coupling

  • Dorothee Günzel
Invited Review

Abstract

Tight junction (TJ) strands between epithelial or endothelial cells are formed by claudins, a protein family comprising up to 27 members in mammals. Although many more proteins are involved in the formation of TJ complexes, claudins are the only TJ proteins that are able to form TJ-like strands when overexpressed in cells that are normally devoid of TJs (e.g., fibroblasts). Within the paracellular cleft, the extracellular domains of claudins provide the matrix that seals the paracellular pathway. However, within this matrix, some claudins act as channels that specifically allow certain ions to cross this barrier. Barrier-forming claudins predominate in epithelia that enclose compartments containing harmful ion concentrations (e.g., H+ in the stomach, K+ in the inner ear endolymph) or high pressures (e.g., in blastocoel or brain ventricle formation during development). Here, even seemingly minor alterations in TJ composition may be detrimental to the organism. In contrast, in many transporting epithelia, channel-forming claudins are essential for transcellular and paracellular transport coupling. Mutation or knockout of channel-forming claudins in these tissues brings both transcellular and paracellular transports to a standstill. The present review will present examples to illustrate the importance of single members of the claudin family in general epithelial transport physiology.

Keywords

Claudin Tight junction Epithelial transport Embryonic development Lumen formation 

Notes

Acknowledgements

I would like to thank Dr. Michael Fromm for his untiring readiness for discussions and his critical reading of this manuscript. Financial support by the Deutsche Forschungsgemeinschaft (DFG grant GU447/14-1) is gratefully acknowledged.

References

  1. 1.
    Amasheh S, Meiri N, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD, Fromm M (2002) Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci 115:4969–4976CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson JM, Van Itallie CM, Fanning AS (2004) Setting up a selective barrier at the apical junction complex. Curr Opin Cell Biol 16:140–145CrossRefPubMedGoogle Scholar
  3. 3.
    Angelow S, Schneeberger EE, Yu AS (2007) Claudin-8 expression in renal epithelial cells augments the paracellular barrier by replacing endogenous claudin-2. J Membr Biol 215:147–159CrossRefPubMedGoogle Scholar
  4. 4.
    Bagnat M, Cheung ID, Mostov KE, Stainier DY (2007) Genetic control of single lumen formation in the zebrafish gut. Nat Cell Biol 9:954–960CrossRefPubMedGoogle Scholar
  5. 5.
    Barmeyer C, Fromm M, Schulzke JD (2017) Active and passive involvement of claudins in the chronically inflamed intestine. Pflügers Arch (present volume)Google Scholar
  6. 6.
    Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K, Gardner DJ, Wilcox ER, Rasmussen J, Anderson JM, Dolan DF, Forge A, Raphael Y, Camper SA, Friedman TB (2003) Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12:2049–2061CrossRefPubMedGoogle Scholar
  7. 7.
    Bäsler K, Brandner JM (2017) Tight junctions in skin inflammation. Pflügers Arch(present volume)Google Scholar
  8. 8.
    Brison DR, Leese HJ (1993) Role of chloride transport in the development of the rat blastocyst. Biol Reprod 48:692–702CrossRefPubMedGoogle Scholar
  9. 9.
    Bronstein JM, Popper P, Micevych PE, Farber DB (1996) Isolation and characterization of a novel oligodendrocyte-specific protein. Neurol 47:772–778CrossRefGoogle Scholar
  10. 10.
    Claude P (1978) Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens. J Membr Biol 39:219–232CrossRefPubMedGoogle Scholar
  11. 11.
    Claude P, Goodenough DA (1973) Fracture faces of zonulae occludentes from “tight” and “leaky” epithelia. J Cell Biol 58:390–400CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Damkier HH, Brown PD, Praetorius J (2013) Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev 93:1847–1892CrossRefPubMedGoogle Scholar
  13. 13.
    Eichner M, Protze J, Piontek A, Krause G, Piontek J (2017) Targeting and alteration of tight junctions by bacteria and their virulence factors such as Clostridium perfringens enterotoxin. Pflügers Arch (present volume)Google Scholar
  14. 14.
    Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Furuse M, Furuse K, Sasaki H, Tsukita S (2001) Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Biol 153:263–272CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S (2002) Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 156:1099–1111CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gong Y, Hou Jianghui (2017) Claudins in barrier and transport function—the kidney. Pflügers Arch (present volume)Google Scholar
  18. 18.
    Gow A, Davies C, Southwood CM, Frolenkov G, Chrustowski M, Ng L, Yamauchi D, Marcus DC, Kachar B (2004) Deafness in claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function. J Neurosci 24:7051–7062CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Green CR, Bergquist PR (1982) Phylogenetic relationships within the invertebrata in relation to the structure of septate junctions and the development of occluding junctional types. J Cell Sci 53:279–305Google Scholar
  20. 20.
    Günzel D, Fromm M (2012) Claudins and other tight junction proteins. Compreh Physiol 2:1819–1852Google Scholar
  21. 21.
    Günzel D, Yu AS (2013) Claudins and the modulation of tight junction permeability. Physiol Rev 93:525–569CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Günzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Müller D (2009) Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci 122:1507–1517CrossRefPubMedGoogle Scholar
  23. 23.
    Günzel D, Zakrzewski S, Schmid T, Pangalos M, Wiedenhoeft J, Blasse C, Ozboda C, Krug SM (2012) From TER to trans- and paracellular resistance: lessons from impedance spectroscopy. Ann N Y Acad Sci 1257:142–151CrossRefPubMedGoogle Scholar
  24. 24.
    Hashimoto Y, Yagi K, Kondoh M (2017) Roles of the first-generation claudin binder, Clostridium perfringens enterotoxin, in the diagnosis and claudin-targeted treatment of epithelium-derived cancers. Pflügers Arch (present volume)Google Scholar
  25. 25.
    Hayashi D, Tamura A, Tanaka H, Yamazaki Y, Watanabe S, Suzuki K, Suzuki K, Sentani K, Yasui W, Rakugi H, Isaka Y, Tsukita S (2012) Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1beta, and atrophic gastritis in mice. Gastroenterology 142:292–304CrossRefPubMedGoogle Scholar
  26. 26.
    Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM (2006) Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns 6:581–588CrossRefPubMedGoogle Scholar
  27. 27.
    Hou J, Shan Q, Wang T, Gomes AS, Yan Q, Paul DL, Bleich M, Goodenough DA (2007) Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. J Biol Chem 282:17114–17122CrossRefPubMedGoogle Scholar
  28. 28.
    Inai T, Kobayashi J, Shibata Y (1999) Claudin-1 contributes to the epithelial barrier function in MDCK cells. Eur J Cell Biol 78:849–855CrossRefPubMedGoogle Scholar
  29. 29.
    Jovov B, Van Itallie CM, Shaheen NJ, Carson JL, Gambling TM, Anderson JM, Orlando RC (2007) Claudin-18: a dominant tight junction protein in Barrett’s esophagus and likely contributor to its acid resistance. Am J Physiol Gastrointest Liver Physiol 293:G1106–G1113CrossRefPubMedGoogle Scholar
  30. 30.
    Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N (1997) Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J Biol Chem 272:26652–26658CrossRefPubMedGoogle Scholar
  31. 31.
    Kirk A, Campbell S, Bass P, Mason J, Collins J (2010) Differential expression of claudin tight junction proteins in the human cortical nephron. Nephrol Dial Transplant 25:2107–2119CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kitajiri SI, Furuse M, Morita K, Saishin-Kiuchi Y, Kido H, Ito J, Tsukita S (2004) Expression patterns of claudins, tight junction adhesion molecules, in the inner ear. Hear Res 187:25–34CrossRefPubMedGoogle Scholar
  33. 33.
    Kitajiri S, Miyamoto T, Mineharu A, Sonoda N, Furuse K, Hata M, Sasaki H, Mori Y, Kubota T, Ito J, Furuse M, Tsukita S (2004) Compartmentalization established by claudin-11-based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential. J Cell Sci 117:5087–5096CrossRefPubMedGoogle Scholar
  34. 34.
    Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886PubMedGoogle Scholar
  35. 35.
    Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell 20:3713–3724CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Krug SM, Günzel D, Conrad MP, Rosenthal R, Fromm A, Amasheh S, Schulzke JD, Fromm M (2012) Claudin-17 forms tight junction channels with distinct anion selectivity. Cell Mol Life Sci 69:2765–2778CrossRefPubMedGoogle Scholar
  37. 37.
    Krug SM, Schulzke JD, Fromm M (2014) Tight junction, selective permeability, and related diseases. Semin Cell Devel Biol 36:166–176CrossRefGoogle Scholar
  38. 38.
    Loh YH, Christoffels A, Brenner S, Hunziker W, Venkatesh B (2004) Extensive expansion of the claudin gene family in the teleost fish, Fugu rubripes. Genome Res 14:1248–1257CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lowery LA, Sive H (2005) Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products. Development 132:2057–2067CrossRefPubMedGoogle Scholar
  40. 40.
    Manejwala FM, Cragoe EJ Jr, Schultz RM (1989) Blastocoel expansion in the preimplantation mouse embryo: role of extracellular sodium and chloride and possible apical routes of their entry. Dev Biol 133:210–220CrossRefPubMedGoogle Scholar
  41. 41.
    Markov AG, Veshnyakova A, Fromm M, Amasheh M, Amasheh S (2010) Segmental expression of claudin proteins correlates with tight junction barrier properties in rat intestine. J Comp Physiol B 180:591–598CrossRefPubMedGoogle Scholar
  42. 42.
    Matsumoto K, Imasato M, Yamazaki Y, Tanaka H, Watanabe M, Eguchi H, Nagano H, Hikita H, Tatsumi T, Takehara T, Tamura A, Tsukita S (2014) Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice. Gastroenterology 147:1134–1145CrossRefPubMedGoogle Scholar
  43. 43.
    Milatz S, Breiderhoff T (2017) One gene, two paracellular ion channels—claudin-10 in the kidney. Pflügers Arch(present volume)Google Scholar
  44. 44.
    Moriwaki K, Tsukita S, Furuse M (2007) Tight junctions containing claudin 4 and 6 are essential for blastocyst formation in preimplantation mouse embryos. Dev Biol 312:509–522CrossRefPubMedGoogle Scholar
  45. 45.
    Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, Furuse K, Sasaki H, Fujimura A, Imai M, Kusano E, Tsukita S, Furuse M (2010) Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci U S A 107:8011–8016CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nakano Y, Kim SH, Kim HM, Sanneman JD, Zhang Y, Smith RJ, Marcus DC, Wangemann P, Nessler RA, Banfi B (2009) A claudin-9-based ion permeability barrier is essential for hearing. PLoS Genet 5:e1000610CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Notarianni E, Hirst BH (1999) Electrogenic sodium transport mediated by an amiloride-sensitive conductance in a porcine trophectoderm cell line. Placenta 20:149–154CrossRefPubMedGoogle Scholar
  49. 49.
    Osanai M, Takasawa A, Murata M, Sawada N (2017) Claudins in cancer: bench to bedside. Pflügers Arch (present volume)Google Scholar
  50. 50.
    Pei L, Solis G, Nguyen MT, Kamat N, Magenheimer L, Zhuo M, Li J, Curry J, McDonough AA, Fields TA, Welch WJ, Yu AS (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509–2518CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, Günzel D, Fromm M (2010) Claudin-2, a component of the tight junction, forms a paracellular water channel. J Cell Sci 123:1913–1921CrossRefPubMedGoogle Scholar
  52. 52.
    Rosenthal R, Günzel D, Krug SM, Schulzke JD, Fromm M, Yu AS (2016) Claudin-2-mediated cation and water transport share a common pore. Acta Physiol (Oxf). doi: 10.1111/apha.12742 Google Scholar
  53. 53.
    Saitoh Y, Suzuki H, Tani K, Nishikawa K, Irie K, Ogura Y, Tamura A, Tsukita S, Fujiyoshi Y (2015) Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science 347:775–778CrossRefPubMedGoogle Scholar
  54. 54.
    Schnermann J, Huang Y, Mizel D (2013) Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol 305:F1352–F1364CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Schultz SG (1972) Electrical potential differences and electromotive forces in epithelial tissues. J Gen Physiol 59:794–798CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Shigemoto T (1999) Two types of external Cl-dependent Cl channels and one type of stretch receptor cation channel contribute to the formation of isotonic blastocoel fluid in early medaka fish embryo. Jpn J Physiol 49:243–255CrossRefPubMedGoogle Scholar
  57. 57.
    Shinoda T, Shinya N, Ito K, Ohsawa N, Terada T, Hirata K, Kawano Y, Yamamoto M, Kimura-Someya T, Yokoyama S, Shirouzu M (2016) Structural basis for disruption of claudin assembly in tight junctions by an enterotoxin. Sci Rep 6:33632CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Sirotkin H, Morrow B, Saint-Jore B, Puech A, Das Gupta R, Patanjali SR, Skoultchi A, Weissman SM, Kucherlapati R (1997) Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 42:245–251CrossRefPubMedGoogle Scholar
  59. 59.
    Staehelin LA (1973) Further observations of the fine structure of freeze-cleaved tight junctions. J Cell Sci 13:763–786PubMedGoogle Scholar
  60. 60.
    Stevenson BR, Anderson JM, Goodenough DA, Mooseker MS (1988) Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance. J Cell Biol 107:2401–2408CrossRefPubMedGoogle Scholar
  61. 61.
    Suzuki H, Nishizawa T, Tani K, Yamazaki Y, Tamura A, Ishitani R, Dohmae N, Tsukita S, Nureki O, Fujiyoshi Y (2014) Crystal structure of a claudin provides insight into the architecture of tight junctions. Science 344:304–307CrossRefPubMedGoogle Scholar
  62. 62.
    Tamura A, Kitano Y, Hata M, Katsuno T, Moriwaki K, Sasaki H, Hayashi H, Suzuki Y, Noda T, Furuse M, Tsukita S (2008) Megaintestine in claudin-15-deficient mice. Gastroenterology 134:523–534CrossRefPubMedGoogle Scholar
  63. 63.
    Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, Tsukita S (2011) Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterology 140:913–923CrossRefPubMedGoogle Scholar
  64. 64.
    Tanaka H, Takechi M, Kiyonari H, Shioi G, Tamura A, Tsukita S (2015) Intestinal deletion of claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice. Gut 64:1529–1538CrossRefPubMedGoogle Scholar
  65. 65.
    Tanaka H, Yamamoto Y, Kashihara H, Yamazaki Y, Tani K, Fujiyoshi Y, Mineta K, Takeuchi K, Tamura A, Tsukita S (2016) Claudin-21 has a paracellular channel role at tight junctions. Mol Cell Biol 36:954–964CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Van Itallie C, Fanning AS, Anderson JM (2003) Reversal of charge selectivity in cation or anion selective epithelial lines by expression of different claudins. Am J Physiol Cell Physiol 286:F1078–F1084CrossRefGoogle Scholar
  67. 67.
    Van Itallie CM, Rogan S, Yu AS, Seminario-Vidal L, Holmes J, Anderson JM (2006) Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Renal Physiol 291:F1288–F1299CrossRefPubMedGoogle Scholar
  68. 68.
    Wada M, Tamura A, Takahashi N, Tsukita S (2013) Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. Gastroenterology 144:369–380CrossRefPubMedGoogle Scholar
  69. 69.
    Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyantseva I, Ben-Yosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Griffith AJ, Friedman TB (2001) Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 104:165–172CrossRefPubMedGoogle Scholar
  70. 70.
    Will C, Breiderhoff T, Thumfart J, Stuiver M, Kopplin K, Sommer K, Günzel D, Querfeld U, Meij IC, Shan Q, Bleich M, Willnow TE, Müller D (2010) Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. Am J Physiol Renal Physiol 298:F1152–F1161CrossRefPubMedGoogle Scholar
  71. 71.
    Zdebik AA, Wangemann P, Jentsch TJ (2009) Potassium ion movement in the inner ear: insights from genetic disease and mouse models. Physiology (Bethesda) 24:307–316CrossRefGoogle Scholar
  72. 72.
    Zeissig S, Burgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD (2007) Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56:61–72CrossRefPubMedGoogle Scholar
  73. 73.
    Zhang J, Piontek J, Wolburg H, Piehl C, Liss M, Otten C, Christ A, Willnow TE, Blasig IE, Abdelilah-Seyfried S (2010) Establishment of a neuroepithelial barrier by Claudin5a is essential for zebrafish brain ventricular lumen expansion. Proc Natl Acad Sci U S A 107:1425–1430CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Zhao Y, Doroshenko PA, Alper SL, Baltz JM (1997) Routes of Cl transport across the trophectoderm of the mouse blastocyst. Dev Biol 189:148–160CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institut für Klinische Physiologie, Campus Benjamin FranklinCharité–UniversitätsmedizinBerlinGermany

Personalised recommendations