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From structure to disease: the evolving tale of aquaporin biology

Key Points

  • Aquaporins are membrane-channel proteins that are present at all levels of life, from bacteria to mammals. Most aquaporins are selectively permeated by water, although some family members are permeated by other small molecules.

  • Aquaporins are present in the membrane as tetramers. Each aquaporin monomer contains its own channel.

  • Structural studies have elucidated the molecular basis for channel selectivity, and are likely to provide insights into the mechanisms by which some members of the family are gated.

  • Eleven mammalian aquaporins have been identified so far and they have cellular and subcellular distributions in different organs that indicate probable functional roles. Studies in animals and humans have revealed that aquaporins participate in a wide range of physiological and pathological processes.

  • Aquaporin regulation across the protein family is complex. It includes transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.

  • The discovery of aquaporins provoked a reconsideration of the mechanisms that underlie the water permeability of membranes. Recognition that membrane water permeability might be regulated independently of solute permeability has provided new insights into organ physiology, and might lead to the identification of aquaporins as targets for novel therapies in pathological conditions in which water homeostasis is disrupted.

Abstract

Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins — the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines.

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Figure 1: The aquaporin family tree.
Figure 2: The structure of aquaporin-1.
Figure 3: Aquaporin distribution in the human kidney.
Figure 4: Aquaporin distribution in the human respiratory tract.
Figure 5: Aquaporin distribution in the human eye.
Figure 6: Aquaporin expression in brain astrocytes.

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References

  1. Agre, P. et al. Aquaporin CHIP: the archetypal molecular water channel. Am. J. Physiol. 265, F463–F476 (1993).

    CAS  PubMed  Google Scholar 

  2. Preston, G. M., Carroll, T. P., Guggino, W. B. & Agre, P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256, 385–387 (1992). This is the initial report of the discovery and biophysical characterization of aquaporin-1, the first molecular water channel to be identified.

    CAS  PubMed  Google Scholar 

  3. Loo, D. D., Wright, E. M. & Zeuthen, T. Water pumps. J. Physiol. 542, 53–60 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Borgnia, M., Nielsen, S., Engel, A. & Agre, P. Cellular and molecular biology of the aquaporin water channels. Annu. Rev. Biochem. 68, 425–458 (1999).

    CAS  PubMed  Google Scholar 

  5. Koyama, Y. et al. Molecular cloning of a new aquaporin from rat pancreas and liver. J. Biol. Chem. 272, 30329–30333 (1997).

    CAS  PubMed  Google Scholar 

  6. Yasui, M. et al. Rapid gating and anion permeability of an intracellular aquaporin. Nature 402, 184–187 (1999). This report highlights the unusual features of AQP6, which, in contrast to most members of the aquaporin family, is an intracellular channel, is gated and is permeated by anions as well as by water.

    CAS  PubMed  Google Scholar 

  7. Ishibashi, K. et al. Cloning and functional expression of a second new aquaporin abundantly expressed in testis. Biochem. Biophys. Res. Commun. 237, 714–718 (1997).

    CAS  PubMed  Google Scholar 

  8. Ma, T., Yang, B. & Verkman, A. S. Cloning of a novel water and urea-permeable aquaporin from mouse expressed strongly in colon, placenta, liver, and heart. Biochem. Biophys. Res. Commun. 240, 324–328 (1997).

    CAS  PubMed  Google Scholar 

  9. Smith, B. L. & Agre, P. Erythrocyte Mr 28,000 transmembrane protein exists as a multisubunit oligomer similar to channel proteins. J. Biol. Chem. 266, 6407–6415 (1991).

    CAS  PubMed  Google Scholar 

  10. Verbavatz, J. M. et al. Tetrameric assembly of CHIP28 water channels in liposomes and cell membranes: a freeze–fracture study. J. Cell Biol. 123, 605–618 (1993).

    CAS  PubMed  Google Scholar 

  11. Preston, G. M. & Agre, P. Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: member of an ancient channel family. Proc. Natl Acad. Sci. USA 88, 11110–11114 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jung, J. S., Preston, G. M., Smith, B. L., Guggino, W. B. & Agre, P. Molecular structure of the water channel through aquaporin CHIP. The hourglass model. J. Biol. Chem. 269, 14648–14654 (1994).

    CAS  PubMed  Google Scholar 

  13. Murata, K. et al. Structural determinants of water permeation through aquaporin-1. Nature 407, 599–605 (2000).

    CAS  PubMed  Google Scholar 

  14. Ren, G., Reddy, V. S., Cheng, A., Melnyk, P. & Mitra, A. K. Visualization of a water-selective pore by electron crystallography in vitreous ice. Proc. Natl Acad. Sci. USA 98, 1398–1403 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu, D. et al. Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290, 481–486 (2000).

    CAS  PubMed  Google Scholar 

  16. Sui, H., Han, B. G., Lee, J. K., Walian, P. & Jap, B. K. Structural basis of water-specific transport through the AQP1 water channel. Nature 414, 872–878 (2001). References 15 and 16 define the atomic structures of GlpF and AQP1, respectively, which are both members of the aquaporin family of proteins.

    CAS  PubMed  Google Scholar 

  17. Kozono, D., Yasui, M., King, L. S. & Agre, P. Aquaporin water channels: atomic structure and molecular dynamics meet clinical medicine. J. Clin. Invest. 109, 1395–1399 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. de Groot, B. L. & Grubmuller, H. Water permeation across biological membranes: mechanism and dynamics of aquaporin-1 and GlpF. Science 294, 2353–2357 (2001).

    CAS  PubMed  Google Scholar 

  19. Tajkhorshid, E. et al. Control of the selectivity of the aquaporin water channel family by global orientational tuning. Science 296, 525–530 (2002).

    CAS  PubMed  Google Scholar 

  20. Nemeth-Cahalan, K. L. & Hall, J. E. pH and calcium regulate the water permeability of aquaporin 0. J. Biol. Chem. 275, 6777–6782 (2000).

    CAS  PubMed  Google Scholar 

  21. Gonen, T., Sliz, P., Kistler, J., Cheng, Y. & Walz, T. Aquaporin-0 membrane junctions reveal the structure of a closed water pore. Nature 429, 193–197 (2004).

    CAS  PubMed  Google Scholar 

  22. Zeuthen, T. & Klaerke, D. A. Transport of water and glycerol in aquaporin 3 is gated by H+. J. Biol. Chem. 274, 21631–21636 (1999).

    CAS  PubMed  Google Scholar 

  23. Zelenina, M., Bondar, A. A., Zelenin, S. & Aperia, A. Nickel and extracellular acidification inhibit the water permeability of human aquaporin-3 in lung epithelial cells. J. Biol. Chem. 278, 30037–30043 (2003).

    CAS  PubMed  Google Scholar 

  24. Han, H., Wax, M. B. & Patil, R. V. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J. Biol. Chem. 273, 6001–6004 (1998).

    CAS  PubMed  Google Scholar 

  25. Zelenia, M., Zelenin, S., Bondar, A. A., Brismar, H. & Aperia, A. Water permeability of aquaporin-4 is deceased by protein kinase C and dopamine. Am. J. Physiol. 283, F309–F318 (2002).

    Google Scholar 

  26. Ikeda, M. et al. Characterization of aquaporin-6 as a nitrate channel in mammalian cells. J. Biol. Chem. 277, 39873–39879 (2002).

    CAS  PubMed  Google Scholar 

  27. Anthony, T. L. et al. Cloned human aquaporin-1 is a cyclic GMP-gated ion channel. Mol. Pharm. 57, 576–588 (2000).

    CAS  Google Scholar 

  28. Saparov, S. M., Kozono, D., Rothe, U., Agre, P. & Pohl, P. Water and ion permeation of aquaporin-1 in planar lipid bilayers. J. Biol. Chem. 276, 31515–31520 (2001).

    CAS  PubMed  Google Scholar 

  29. Nakhoul, N. L., Davis, B. A., Romero, M. F. & Boron, W. F. Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. Am. J. Physiol. 274, C543–548 (1998).

    CAS  PubMed  Google Scholar 

  30. Cooper, G. J. & Boron, W. F. Effect of PCMBS on CO2 permeability of Xenopus oocytes expressing aquaporin-1 or its C189S mutant. Am. J. Physiol. 275, C1481–C1486 (1998).

    CAS  PubMed  Google Scholar 

  31. Prasad, G. V., Coury, L. A., Fin, F. & Zeidel, M. L. Reconstituted aquaporin 1 water channels transport CO2 across membranes. J. Biol. Chem. 273, 33123–33126 (1998).

    CAS  PubMed  Google Scholar 

  32. Yang, B. et al. Carbon dioxide permeability of aquaporin-1 measured in erthrocytes and lung of aquaporin-1 null mice and in reconstituted liposomes. J. Biol. Chem. 275, 2686–2692 (2000).

    CAS  PubMed  Google Scholar 

  33. Fang, X., Yang, B., Matthay, M. A. & Verkman, A. S. Evidence against aquaporin-1 dependent CO2 permeability in lung and kidney. J. Physiol. 542, 63–69 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cooper, G. J., Zhou, Y., Bouyer, P., Grichtchenko, I. I. & Boron, W. F. Transport of volatile solutes through AQP1. J. Physiol. 542, 17–29 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Verkman, A. S. Does aquaporin-1 pass gas? An opposing view. J. Physiol. 542, 31 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Uehlein, N., Lovisolo, C., Siefritz, F. & Kaldenhoff, R. The tobacco aquaporin NtAQP1 is a membrane CO2 pore with physiological functions. Nature 425, 734–737 (2003). Describes the physiological impact of aquaporin-mediated CO 2 permeability on photosynthesis and leaf growth in plants.

    CAS  PubMed  Google Scholar 

  37. Nielsen, S. et al. Aquaporins in the kidney: from molecules to medicine. Physiol. Rev. 82, 205–244 (2002).

    CAS  PubMed  Google Scholar 

  38. Ma, T. et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J. Biol. Chem. 273, 4296–4299 (1998). This description of renal function in Aqp1 -null mice provided convincing evidence for a physiological role for AQP1 in the kidney.

    CAS  PubMed  Google Scholar 

  39. Schnermann, J. et al. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc. Natl Acad. Sci. USA 95, 9660–9664 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pallone, T. L., Edwards, A., Ma, T., Silldorff, E. P. & Verkman, A. S. Requirement of aquaporin-1 for NaCl-driven water transport across descending vasa recta. J. Clin. Invest. 105, 215–222 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Smith, B. L., Preston, G. M., Spring, F. A., Anstee, D. J. & Agre, P. Human red cell aquaporin CHIP. I. Molecular characterization of ABH and Colton blood group antigens. J. Clin. Invest. 94, 1043–1049 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Preston, G. M., Smith, B. L., Zeidel, M. L., Moulds, J. J. & Agre, P. Mutations in aquaporin-1 in phenotypically normal humans without functional CHIP water channels. Science 265, 1585–1587 (1994).

    CAS  PubMed  Google Scholar 

  43. King, L. S., Choi, M., Fernandez, P. C., Cartron, J. P. & Agre, P. Defective urinary-concentrating ability due to a complete deficiency of aquaporin-1. N. Engl. J. Med. 345, 175–179 (2001).

    CAS  PubMed  Google Scholar 

  44. Robertson, G. L. Differential diagnosis of polyuria. Annu. Rev. Med. 39, 425–442 (1988).

    CAS  PubMed  Google Scholar 

  45. Brown, D. The ins and outs of aquaporin-2 trafficking. Am. J. Physiol. 284, F893–F901 (2003).

    CAS  Google Scholar 

  46. Wade, J. B., Stetson, D. L. & Lewis, S. A. ADH action: evidence for a membrane shuttle mechanism. Ann. NY Acad. Sci. 372, 106–117 (1981).

    CAS  PubMed  Google Scholar 

  47. van Balkom, B. W. et al. Hypertonicity is involved in redirecting the aquaporin-2 water channel into the basolateral, instead of the apical, plasma membrane of renal epithelial cells. J. Biol. Chem. 278, 1101–1107 (2003).

    CAS  PubMed  Google Scholar 

  48. Edwards, R. M., Jackson, B. A. & Dousa, T. P. ADH-sensitive cAMP system in papillary collecting duct: effect of osmolality and PGE2. Am. J. Physiol. 240, F311–F318 (1981).

    CAS  PubMed  Google Scholar 

  49. Fushimi, K., Sasaki, S. & Marumo, F. Phosphorylation of serine 256 is required for cAMP-dependent regulatory exocytosis of the aquaporin-2 water channel. J. Biol. Chem. 272, 14800–14804 (1997).

    CAS  PubMed  Google Scholar 

  50. Katsura, T., Gustafson, C. E., Ausiello, D. A. & Brown, D. Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. Am. J. Physiol. 272, F817–F822 (1997).

    CAS  PubMed  Google Scholar 

  51. Marples, D. et al. Dynein and dynactin colocalize with AQP2 water channels in intracellular vesicles from kidney collecting duct. Am. J. Physiol 274, F384–F394 (1998).

    CAS  PubMed  Google Scholar 

  52. Nielsen, S. et al. Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. J. Clin. Invest. 96, 1834–1844 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Inoue, T. et al. SNAP-23 in rat kidney: colocalization with aquaporin-2 in collecting duct vesicles. Am. J. Physiol. 275, F752–F760 (1998).

    CAS  PubMed  Google Scholar 

  54. Gouraud, S. et al. Functional involvement of VAMP/synaptobrevin-2 in cAMP-stimulated aquaporin 2 translocation in renal collecting duct cells. J. Cell Sci. 115, 3667–3674 (2002).

    CAS  PubMed  Google Scholar 

  55. van Balkom, V. W. M. et al. The role of putative phosphorylation sites in the targeting and shuttling of the aquaporin-2 water channel. J. Biol. Chem. 277, 41473–41479 (2003).

    Google Scholar 

  56. Valenti, G. et al. A heterotrimeric G protein of the G1 family is required for cAMP-triggered trafficking of aquaporin 2 in kidney epithelial cells. J. Biol. Chem. 273, 22627–22634 (1998).

    CAS  PubMed  Google Scholar 

  57. Klussmann, E. et al. An inhibitory role of rho in the vasopressin-mediated translocation of aquaporin-2 into cell membranes of renal principal cells. J. Biol. Chem. 276, 20451–20457 (2001).

    CAS  PubMed  Google Scholar 

  58. Bouley, R. et al. Nitric oxide and atrial natriuretic factor stimulate cGMP-dependent membrane insertion of aquaporin 2 in renal epithelial cells. J. Clin. Invest. 106, 1115–1126 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Deen, P. M. et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264, 92–95 (1994). These investigators provided the first example of an aquaporin mutation that has physiological consequences in humans.

    CAS  PubMed  Google Scholar 

  60. Mulders, S. M. et al. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J. Clin. Invest. 102, 57–66 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kamsteeg, E. J., Wormhoudt, T. A., Rijss, J. P., van Os, C. H. & Deen, P. M. An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. EMBO J. 18, 2394–2400 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Marples, D., Christensen, S., Christensen, E. I., Ottosen, P. D. & Nielsen, S. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J. Clin. Invest. 95, 1838–1845 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Frøkiær, J., Marples, D., Knepper, M. A. & Nielsen, S. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am. J. Physiol. 270, F657–F668 (1996).

    PubMed  Google Scholar 

  64. Marples, D., Frøkiær, J., Dorup, J., Knepper, M. A. & Nielsen, S. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J. Clin. Invest. 97, 1960–1968 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Nielsen, S. et al. Congestive heart failure in rats is associated with increased expression and targeting of aquaporin-2 water channel in collecting duct. Proc. Natl Acad. Sci. USA 94, 5450–5455 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Schrier, R. W. & Martin, P. Y. Recent advances in the understanding of water metabolism in heart failure. Adv. Exp. Med. Biol. 449, 415–426 (1998).

    CAS  PubMed  Google Scholar 

  67. Ma, T. et al. Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J. Clin. Invest. 100, 957–962 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ma, T. et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc. Natl Acad. Sci. USA 97, 4386–4391 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Roudier, N. et al. AQP3 deficiency in humans and the molecular basis of a novel blood group system, GIL. J. Biol. Chem. 277, 45854–45859 (2002).

    CAS  PubMed  Google Scholar 

  70. Nielsen, S., King, L. S., Christensen, B. M. & Agre, P. Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat. Am. J. Physiol. 273, C1549–C1561 (1997).

    CAS  PubMed  Google Scholar 

  71. Kreda, S. M., Gynn, M. C., Fenstermacher, D. A., Boucher, R. C. & Gabriel, S. E. Expression and localization of epithelial aquaporins in the adult human lung. Am. J. Respir. Cell Mol. Biol. 24, 224–234 (2001).

    CAS  PubMed  Google Scholar 

  72. Krane, C. M. et al. Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation. Proc. Natl Acad. Sci. USA 98, 14114–14119 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. King, L. S. & Agre, P. Man is not a rodent: aquaporins in the airways. Am. J. Respir. Cell Mol. Biol. 24, 221–223 (2001).

    CAS  PubMed  Google Scholar 

  74. Borok, Z. et al. Keratinocyte growth factor modulates alveolar epithelial cell phenotype in vitro: expression of aquaporin 5. Am. J. Respir. Cell Mol. Biol. 18, 554–561 (1998).

    CAS  PubMed  Google Scholar 

  75. King, L. S., Nielsen, S. & Agre, P. Aquaporin-1 water channel protein in lung: ontogeny, steroid-induced expression, and distribution in rat. J. Clin. Invest. 97, 2183–2191 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. King, L. S., Nielsen, S. & Agre, P. Aquaporins in complex tissues. I. Developmental patterns in respiratory and glandular tissues of rat. Am. J. Physiol. 273, C1541–C1548 (1997).

    CAS  PubMed  Google Scholar 

  77. Moon, C., King, L. S. & Agre, P. Aqp1 expression in erythroleukemia cells: genetic regulation of glucocorticoid and chemical induction. Am. J. Physiol. 273, C1562–C1570 (1997).

    CAS  PubMed  Google Scholar 

  78. Leitch, V., Agre, P. & King, L. S. Altered ubiquitination and stability of aquaporin-1 in hypertonic stress. Proc. Natl Acad. Sci. USA 98, 2894–2898 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Towne, J. E., Krane, C. N., Bachurski, C. J. & Menon, A. G. Tumor necrosis factor-α inhibits aquaporin 5 expression in mouse lung epithelial cells. J. Biol. Chem. 276, 18657–18664 (2001).

    CAS  PubMed  Google Scholar 

  80. Yang, F., Kawedia, J. D. & Menon, A. G. Cyclic AMP regulates aquaporin 5 expression at both transcriptional and post-transcriptional levels through a protein kinase A pathway. J. Biol. Chem. 278, 32173–32180 (2003).

    CAS  PubMed  Google Scholar 

  81. Hoffert, J. D., Leitch, V., Agre, P. & King, L. S. Hypertonic induction of aquaporin-5 expression through an ERK-dependent pathway. J. Biol. Chem. 275, 9070–9077 (2000).

    CAS  PubMed  Google Scholar 

  82. Jayaraman, S., Song, Y., Vetrivel, L., Shankar, L. & Verkman, A. S. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J. Clin. Invest. 107, 317–324 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hunt, J. F. et al. Endogenous airway acidification: implication for asthma pathophysiology. Am. J. Respir. Crit. Care Med. 161, 694–699 (2000).

    CAS  PubMed  Google Scholar 

  84. Ballard, S. T., Trout, L., Bebok, Z., Sorscher, E. J. & Crews, A. CFTR involvement in chloride, bicarbonate, and liquid secretion by airway submucosal glands. Am. J. Physiol. 277, L694–L699 (1999).

    CAS  PubMed  Google Scholar 

  85. Song, Y. & Verkman, A. S. Aquaporin-5 dependent fluid secretion in airway submucosal glands. J. Biol. Chem. 276, 41288–41292 (2001).

    CAS  PubMed  Google Scholar 

  86. James, A. L., Hogg, J. C., Dunn, L. A. & Pare, P. D. The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening. Am. Rev. Respir. Dis. 138, 136–139 (1988).

    CAS  PubMed  Google Scholar 

  87. Anderson, S. D. & Daviskas, E. The mechanism of exercise-induced asthma is... J. Allergy Clin. Immunol. 106, 453–459 (2000).

    CAS  PubMed  Google Scholar 

  88. Bai, C. et al. Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice. J. Clin. Invest. 103, 555–561 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. King, L. S., Nielsen, S., Agre, P. & Brown, R. H. Decreased pulmonary vascular permeability in aquaporin-1-null humans. Proc. Natl Acad. Sci. USA 99, 1059–1063 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Brown, R. H., Zerhouni, E. A. & Mitzner, W. Visualization of airway obstruction in vivo during pulmonary vascular engorgement and edema. J. Appl. Physiol. 78, 1070–1078 (1995).

    CAS  PubMed  Google Scholar 

  91. Dobbs, L. G. et al. Highly water-permeable type I alveolar epithelial cells confer high water permeability between the airspace and vasculature in rat lung. Proc. Natl Acad. Sci. USA 95, 2991–2996 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Bai, C. et al. Lung fluid transport in aquaporin-1 and aquaporin-5 knockout mice. J. Clin. Invest. 103, 555–561 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Ma, T., Fukuda, N., Song, Y., Matthay, M. A. & Verkman, A. S. Lung fluid transport in aquaporin-5 knockout mice. J. Clin. Invest. 105, 93–100 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Towne, J. E., Harrod, K. S., Krane, C. M. & Menon, A. G. Decreased expression of aquaporin AQP1 and AQP5 in mouse lung after acute viral infection. Am. J. Respir. Cell Mol. Biol. 22, 34–44 (2000).

    CAS  PubMed  Google Scholar 

  95. Leikauf, G. D. et al. Pathogenomic mechanisms for particulate matter induction of acute lung injury and inflammation in mice. Res. Resp. Health Eff. Inst. 105, 5–58 (2001).

    Google Scholar 

  96. Ma, T., Fukuda, N., Song, Y., Matthay, M. A. & Verkman, A. S. Lung fluid transport in aquaporin-5 knockout mice. J. Clin. Invest. 105, 93–100 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Song, Y. et al. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury. J. Physiol. 525, 771–779 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hamann, S. et al. Aquaporins in complex tissues: distribution of aquaporins 1–5 in human and rat eye. Am. J. Physiol. 274, C1332–C1345 (1998).

    CAS  PubMed  Google Scholar 

  99. Mulders, S. M. et al. Water channel properties of major intrinsic protein of lens. J. Biol. Chem. 270, 9010–9016 (1995).

    CAS  PubMed  Google Scholar 

  100. Shiels, A. & Bassnett, S. Mutations in the founder of the MIP gene family underlie cataract development in the mouse. Nature Genet. 12, 212–215 (1996).

    CAS  PubMed  Google Scholar 

  101. Berry, V., Francis, P., Kaushal, S., Moore, A. & Bhattacharya, S. Missense mutations in MIP underlie autosomal dominant 'polymorphic' and lamellar cataracts linked to 12q. Nature Genet. 25, 15–17 (2000).

    CAS  PubMed  Google Scholar 

  102. Francis, P. et al. Functional impairment of lens aquaporin in two families with dominantly inherited cataracts. Hum. Mol. Genet. 9, 2329–2334 (2000).

    CAS  PubMed  Google Scholar 

  103. Thiagarajah, J. R. & Verkman, A. S. Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling. J. Biol. Chem. 277, 19139–19144 (2002).

    CAS  PubMed  Google Scholar 

  104. Zhang, D., Vetrivel, L. & Verkman, A. S. Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production. J. Gen. Physiol. 119, 561–569 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Raina, S., Preston, G. M., Guggino, W. B. & Agre, P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J. Biol. Chem. 270, 1908–1912 (1995).

    CAS  PubMed  Google Scholar 

  106. Gresz, V. et al. Identification and localization of aquaporin water channels in human salivary glands. Am. J. Physiol. 281, G247–G254 (2001).

    CAS  Google Scholar 

  107. Steinfeld, S. et al. Abnormal distribution of aquaporin-5 water channel protein in salivary glands from Sjogren's syndrome patients. Lab. Invest. 81, 143–148 (2001).

    CAS  PubMed  Google Scholar 

  108. Tsubota, K., Hirai, S., King, L. S., Agre, P. & Ishida, N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjogren's syndrome. Lancet 357, 688–689 (2001).

    CAS  PubMed  Google Scholar 

  109. Beroukas, D., Hiscock, J., Jonsson, R., Waterman, S. A. & Gordon, T. P. Subcellular distribution of aquaporin 5 in salivary glands in primary Sjogren's syndrome. Lancet 358, 1875–1876 (2001).

    CAS  PubMed  Google Scholar 

  110. Ma, T. et al. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J. Biol. Chem. 274, 20071–20074 (1999).

    CAS  PubMed  Google Scholar 

  111. Krane, C. M. et al. Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J. Biol. Chem. 276, 23413–23420 (2001).

    CAS  PubMed  Google Scholar 

  112. Nejsum, L. M. et al. Functional requirement of aquaporin-5 in plasma membranes of sweat glands. Proc. Natl Acad. Sci. USA 99, 511–516 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Song, Y., Sonawane, N. & Verkman, A. S. Localization of aquaporin-5 in sweat glands and functional analysis using knockout mice. J. Physiol. 54, 561–568 (2002).

    Google Scholar 

  114. Moore, M., Ma, T., Yang, B. & Verkman, A. S. Tear secretion by lacrimal glands in transgenic mice lacking water channels AQP1, AQP3, AQP4, and AQP5. Exp. Eye Res. 70, 557–562 (2000).

    CAS  PubMed  Google Scholar 

  115. Umenishi, F. & Schrier, R. W. Hypertonicity-induced aquaporin-1 (AQP1) expression is mediated by the activation of MAPK pathway and hypertonicity-responsive element in the AQP1 gene. J. Biol. Chem. 278, 15765–15770 (2003).

    CAS  PubMed  Google Scholar 

  116. Badaut, J., Lasbennes, F., Magistretti, P. J. & Regli, L. Aquaporins in brain: distribution, physiology, and pathophysiology. J. Cereb. Blood Flow Metab. 22, 367–378 (2002).

    CAS  PubMed  Google Scholar 

  117. Nielsen, S. et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci. 17, 171–180 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Amiry-Moghaddam, M. & Otterson, O. P. The molecular basis of water transport in the brain. Nature Rev. Neurosci. 4, 991–1001 (2003).

    CAS  Google Scholar 

  119. Amiry-Moghaddam, M. et al. α syntrophin deletion removes the perivascular but not the endothelial pool of aquaporin-4 at the blood–brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J. 18, 542–544 (2004).

    CAS  PubMed  Google Scholar 

  120. Neely, J. D. et al. Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc. Natl Acad. Sci. USA 98, 14108–14113 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Hung, A. Y. & Sheng, M. PDZ domains: structural modules for protein complex assembly. J. Biol. Chem. 277, 5699–5702 (2002).

    CAS  PubMed  Google Scholar 

  122. Madrid, R. et al. Polarized trafficking and surface expression of the AQP4 water channel are coordinated by serial and regulated interactions with different clathrin-adaptor complexes. EMBO J. 20, 7008–7021 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Monaco, A. P. et al. Isolation of candidate cDNAs for portions of the Duchenne muscular dystophy gene. Nature 323, 646–650 (1986).

    CAS  PubMed  Google Scholar 

  124. Frigeri, A. et al. Muscle loading modulates aquaporin-4 expression in skeletal muscle. FASEB J. 15, 1282–1284 (2001).

    CAS  PubMed  Google Scholar 

  125. Amiry-Moghadam, M. et al. An α-syntrophin dependent pool of AQP4 in astroglial end-feet confers bi-directional water flow between blood and brain. Proc. Natl Acad. Sci. USA 100, 2106–2111 (2003).

    Google Scholar 

  126. Manley, G. T. et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nature Med. 6, 159–163 (2000). These researchers show that the absence of AQP4 in the brain is protective against oedema formation in two models of brain oedema.

    CAS  PubMed  Google Scholar 

  127. Vajde, Z. et al. Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice. Proc. Natl Acad. Sci. USA 99, 13131–13136 (2002).

    Google Scholar 

  128. Nielsen, S., Smith, B. L., Christensen, E. I. & Agre, P. Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc. Natl Acad. Sci. USA 90, 7275–7279 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Elkjaer, M. et al. Immunolocalization of AQP9 in liver, epididymis, testis, spleen, and brain. Biochem. Biophys. Res. Commun. 276, 1118–1128 (2000).

    CAS  PubMed  Google Scholar 

  130. Ma, T., Hara, M., Sougrat, R., Verbavatz, J. -M. & Verkman, A. S. Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3. J. Biol. Chem. 277, 17147–17153 (2002).

    CAS  PubMed  Google Scholar 

  131. Hara, M. & Verkman, A. S. Glycerol replacement corrects defective skin hydration, elasticity and barrier function in aquaporin-3-deficient mice. Proc. Natl Acad. Sci. USA 100, 7360–7365 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Burghardt, B. et al. Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas. Gut 52, 1008–1016 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Beitz, E., Kumagami, H., Krippeit-Drews, P., Ruppersberg, J. P. & Schultz, J. E. Expression pattern of aquaporin water channels in the inner ear of the rat. Hear. Res. 132, 76–84 (1999).

    CAS  PubMed  Google Scholar 

  134. Beitz, E., Zenner, H. P. & Schultz, J. E. Aquaporin-mediated fluid regulation in the inner ear. Cell Mol. Neurobiol. 23, 315–329 (2003).

    CAS  PubMed  Google Scholar 

  135. Li, J. & Verkman, A. S. Impaired hearing in mice lacking aquaporin-4 water channels. J. Biol. Chem. 276, 31233–31237 (2001).

    CAS  PubMed  Google Scholar 

  136. Richard, C., Gao, J., Brown, N. & Reese, J. Aquaporin water channel genes are differentially expressed and regulated by ovarian steroids during the periimplantation period in the mouse. Endocrinology 144, 1533–1541 (2003).

    CAS  PubMed  Google Scholar 

  137. Calamita, G., Mazzone, A., Bizzoca, A. & Svelto, M. Possible involvement of aquaporin-7 and -8 in rats testis development and spermatogenesis. Biochem. Biophys. Res. Commun. 288, 619–625 (2001).

    CAS  PubMed  Google Scholar 

  138. Kishida, K. et al. Aquaporin adipose, a putative glycerol channel in adipocytes. J. Biol. Chem. 275, 20896–20902 (2000).

    CAS  PubMed  Google Scholar 

  139. Kondo, H. et al. Human aquaporin adipose (AQPao) gene. Genomic structure, promoter analysis and functional mutation. Eur. J. Biochem. 269, 1814–1826 (2002).

    CAS  PubMed  Google Scholar 

  140. Carbrey, J. M. et al. Aquaglyceroporin AQP9: solute permeation and metabolic control of expression in liver. Proc. Natl Acad. Sci. USA 100, 2945–2950 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Liu, Z. et al. Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc. Natl Acad. Sci. USA 99, 6053–6058 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. King, L. S. & Yasui, M. Aquaporins and disease: lessons from mice to humans. Trends Endocrin. Metab. 13, 355–360 (2002).

    CAS  Google Scholar 

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Acknowledgements

The authors receive support from the National Heart, Lung and Blood Institute (L.S.K. and P.A.) and the National Eye Institute (P.A.) of the National Institutes of Health, USA, and from the American Heart Association (L.S.K.).

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DATABASES

Entrez

AqpZ

GlpF

Interpro

PDZ domain

OMIM

autosomal dominant NDI

autosomal recessive NDI

Sjögren's syndrome

Protein Data Bank

1J4N

Swiss-Prot

AQP0

AQP1

AQP2

AQP3

AQP4

AQP5

AQP6

AQP7

AQP8

AQP9

AQP10

Glossary

FREEZE–FRACTURE

A technique that allows the examination of membrane proteins by first freezing and then fracturing a tissue to separate the inner and outer leaflets of the membrane bilayer. This technique can be particularly useful for the examination of integral membrane proteins and cell junctions.

DIPOLE

A pair of equal and opposite electrical charges that are located only a short distance apart, for example, at either end of a small molecule.

SERUM OSMOLALITY

A measure of the solute concentration in a particular solution, including biological solutions such as blood or urine. The units for osmolality are milliosmoles of solute per kg of solvent (mosmol kg−1).

TUBULOGLOMERULAR FEEDBACK

The process by which increased fluid and solute delivery out of the proximal tubule feeds back to reduce glomerular filtration and to limit the loss of urine volume.

PNEUMOCYTES

In common usage, this term is applied to the two principal epithelial cell types that line the alveoli of the lungs. Type-I pneumocytes are large flat cells, and type-II pneumocytes are cuboidal cells.

OSMOTIC WATER PERMEABILITY

The permeability of a membrane to water in response to an osmotic gradient across the membrane.

HYDROSTATIC PERMEABILITY

The permeability of a membrane in response to a pressure gradient across the membrane.

OEDEMA

Excess fluid in a particular tissue or anatomic compartment. Swelling in the legs and excess fluid in the airspaces of the lung are examples of oedema.

CATARACTS

Opacities in the lens of the eye that are formed by precipitated proteins or degraded cells and that markedly decrease vision by interfering with the passage of light through the lens.

SCLERAL FIBROBLASTS

Fibroblasts that are found in the sclera, the tissue that forms the white part of the eye.

KERATINOCYTES

Epithelial cells of the skin that have differentiated to produce keratin. Keratinocytes are the predominant cell type in the epidermis of the skin.

TRABECULAR MESHWORK

An anatomic structure at the outer border of the anterior chamber of the eye. This structure consists of a network of endothelial-cell-covered strands that resorb the liquid that is found in the anterior chamber of the eye (aqueous humor).

CANALS OF SCHLEMM

Tubular channels in the eye that are found at the junction of the cornea and sclera, and through which aqueous humor drains.

MYOEPITHELIAL CELLS

Contractile epithelial-like cells that function like smooth muscle, but are usually found between secretory cells and the basement membrane in glands. They have long cytoplasmic extensions, which contain actin bands that can contract to facilitate fluid movement out of the secretory gland.

CHOROID PLEXUS

A collection of villous-like processes at select sites in the ventricular system of the brain. These processes contain a special secretory epithelium that secretes cerebrospinal fluid.

CYSTIC FIBROSIS TRANSMEMBRANE-CONDUCTANCE REGULATOR

(CFTR). This protein forms a chloride channel, is present in many tissues including the lung, kidney and pancreas, and is mutated in cystic fibrosis.

GLUCONEOGENESIS

The process by which glucose is made from amino acids or glycerol in the fasting state. This process occurs primarily in the liver.

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King, L., Kozono, D. & Agre, P. From structure to disease: the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol 5, 687–698 (2004). https://doi.org/10.1038/nrm1469

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