Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Aquaporin water channels in the nervous system

Nature Reviews Neuroscience volume 14, pages 265–277 (2013)Cite this article

Subjects

Key Points

  • Aquaporins (AQPs) are water channel proteins that increase cell membrane water permeability and assemble in cell membranes as tetramers.

  • AQP4, the main water channel in the CNS, is expressed in astrocytes and facilitates the formation and elimination of CNS oedema, modulates neuronal excitability and enhances astrocyte migration.

  • AQP4 also has a role in sensory perception, including vision, hearing and olfaction.

  • Autoantibodies against AQP4 cause neuromyelitis optica, an inflammatory demyelinating disease of the CNS.

  • Aquaporins are also expressed in the peripheral and enteric nervous systems, although their functions at these sites are not known.

Abstract

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sequence and structural features of AQP4.
Figure 2: Aquaporin expression in the nervous system.
Figure 3: Routes of water flow into and out of the CNS in brain oedema.
Figure 4: Aquaporin 4 involvement in astrocyte migration and neuroexcitation.
Figure 5: Proposed role of aquaporin 4 in the pathogenesis of neuromyelitis optica.

Similar content being viewed by others

References

  1. 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). This paper reports the discovery of water channel proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Carbrey, J. M. & Agre, P. Discovery of the aquaporins and development of the field. Handb Exp. Pharmacol. 190, 3–28 (2009).

    CAS  Google Scholar 

  3. Verkman, A. S. Aquaporins in clinical medicine. Annu. Rev. Med. 63, 303–316 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Soveral, G., Prista, C., Moura, T. F. & Loureiro-Dias, M. C. Yeast water channels: an overview of orthodox aquaporins. Biol. Cell 103, 35–54 (2010).

    Article  PubMed  CAS  Google Scholar 

  5. Tanghe, A., Van Dijck, P. & Thevelein, J. M. Why do microorganisms have aquaporins? Trends Microbiol. 14, 78–85 (2006).

    Article  PubMed  CAS  Google Scholar 

  6. Wu, B. & Beitz, E. Aquaporins with selectivity for unconventional permeants. Cell. Mol. Life Sci. 64, 2413–2421 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Rojek, A., Praetorius, J., Frokiaer, J., Nielsen, S. & Fenton, R. A. A current view of the mammalian aquaglyceroporins. Annu. Rev. Physiol. 70, 301–327 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Herrera, M. & Garvin, J. L. Aquaporins as gas channels. Pflugers Arch. 462, 623–630 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Geers, C. & Gros, G. Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol. Rev. 80, 681–715 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Walz, T., Fujiyoshi, Y. & Engel, A. The AQP structure and functional implications. Handb Exp. Pharmacol. 190, 31–56 (2009).

    CAS  Google Scholar 

  11. Ho, J. D. et al. Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance. Proc. Natl Acad. Sci. USA 106, 7437–7442 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cui, Y. & Bastien, D. A. Water transport in human aquaporin-4: molecular dynamics (MD) simulations. Biochem. Biophys. Res. Commun. 412, 654–659 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Hub, J. S., Grubmuller, H. & de Groot, B. L. Dynamics and energetics of permeation through aquaporins. What do we learn from molecular dynamics simulations? Handb Exp. Pharmacol. 190, 57–76 (2009).

    CAS  Google Scholar 

  14. Yang, B., Brown, D. & Verkman, A. S. The mercurial insensitive water channel (AQP-4) forms orthogonal arrays in stably transfected Chinese hamster ovary cells. J. Biol. Chem. 271, 4577–4580 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Verbavatz, J. M., Ma, T., Gobin, R. & Verkman, A. S. Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4. J. Cell Sci. 110, 2855–2860 (1997).

    CAS  PubMed  Google Scholar 

  16. Wolburg, H., Wolburg-Buchholz, K., Fallier-Becker, P., Noell, S. & Mack, A. F. Structure and functions of aquaporin-4-based orthogonal arrays of particles. Int. Rev. Cell Mol. Biol. 287, 1–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Rash, J. E., Yasumura, T., Hudson, C. S., Agre, P. & Nielsen, S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc. Natl Acad. Sci. USA 95, 11981–11986 (1998). This paper provides one of the earliest descriptions of AQP4 expression in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rossi, A., Moritz, T. J., Ratelade, J. & Verkman, A. S. Super-resolution imaging of aquaporin-4 orthogonal arrays of particles in cell membranes. J. Cell Sci. 125, 4405–4412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Neely, J. D., Christensen, B. M., Nielsen, S. & Agre, P. Heterotetrameric composition of aquaporin-4 water channels. Biochemistry 38, 11156–11163 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Jin, B. J., Rossi, A. & Verkman, A. S. Model of aquaporin-4 supramolecular assembly in orthogonal arrays based on heterotetrameric association of M1-M23 isoforms. Biophys. J. 100, 2936–2945 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Crane, J. M. & Verkman, A. S. Determinants of aquaporin-4 assembly in orthogonal arrays revealed by live-cell single-molecule fluorescence imaging. J. Cell Sci. 122, 813–821 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fenton, R. A. et al. Differential water permeability and regulation of three aquaporin 4 isoforms. Cell. Mol. Life Sci. 67, 829–840 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Hiroaki, Y. et al. Implications of the aquaporin-4 structure on array formation and cell adhesion. J. Mol. Biol. 355, 628–639 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Rossi, A., Ratelade, J., Papadopoulos, M. C., Bennett, J. L. & Verkman, A. S. Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly. Glia 60, 2027–2039 (2013).

    Article  Google Scholar 

  25. Zhang, H. & Verkman, A. S. Evidence against involvement of aquaporin-4 in cell–cell adhesion. J. Mol. Biol. 382, 1136–1143 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Furman, C. S. et al. Aquaporin-4 square array assembly: opposing actions of M1 and M23 isoforms. Proc. Natl Acad. Sci. USA 100, 13609–13614 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Papadopoulos, M. C., Manley, G. T., Krishna, S. & Verkman, A. S. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 18, 1291–1293 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Oshio, K. et al. Expression of aquaporin water channels in mouse spinal cord. Neuroscience 127, 685–693 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Nagelhus, E. A. et al. Aquaporin-4 water channel protein in the rat retina and optic nerve: polarized expression in Müller cells and fibrous astrocytes. J. Neurosci. 18, 2506–2519 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Noell, S. et al. Effects of agrin on the expression and distribution of the water channel protein aquaporin-4 and volume regulation in cultured astrocytes. Eur. J. Neurosci. 26, 2109–2118 (2007).

    Article  PubMed  Google Scholar 

  33. Wolburg, H., Noell, S., Wolburg-Buchholz, K., Mack, A. & Fallier-Becker, P. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood–brain barrier. Neuroscientist 15, 180–193 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Saadoun, S., Papadopoulos, M. C., Davies, D. C., Krishna, S. & Bell, B. A. Aquaporin-4 expression is increased in oedematous human brain tumours. J. Neurol. Neurosurg. Psychiatry 72, 262–265 (2002). This is the first demonstration of increased AQP expression in tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Solenov, E., Watanabe, H., Manley, G. T. & Verkman, A. S. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am. J. Physiol. Cell. Physiol. 286, C426–C432 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Nicchia, G. P. et al. Aquaporin-4-containing astrocytes sustain a temperature- and mercury-insensitive swelling in vitro. Glia 31, 29–38 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Hsu, M. S. et al. Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. Neuroscience 178, 21–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Binder, D. K. et al. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53, 631–636 (2006).

    Article  PubMed  Google Scholar 

  39. Padmawar, P., Yao, X., Bloch, O., Manley, G. T. & Verkman, A. S. K+ waves in brain cortex visualized using a long-wavelength K+-sensing fluorescent indicator. Nature Methods 2, 825–827 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Amiry-Moghaddam, M. et al. Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of α-syntrophin-null mice. Proc. Natl Acad. Sci. USA 100, 13615–13620 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Oshio, K., Watanabe, H., Song, Y., Verkman, A. S. & Manley, G. T. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J. 19, 76–78 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Wilson, A. J., Carati, C. J., Gannon, B. J., Haberberger, R. & Chataway, T. K. Aquaporin-1 in blood vessels of rat circumventricular organs. Cell Tissue Res. 340, 159–168 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Dolman, D., Drndarski, S., Abbott, N. J. & Rattray, M. Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J. Neurochem. 93, 825–833 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Saadoun, S., Papadopoulos, M. C., Davies, D. C., Bell, B. A. & Krishna, S. Increased aquaporin 1 water channel expression in human brain tumours. Br. J. Cancer 87, 621–623 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Badaut, J. et al. Distribution of Aquaporin 9 in the adult rat brain: preferential expression in catecholaminergic neurons and in glial cells. Neuroscience 128, 27–38 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Shields, S. D., Mazario, J., Skinner, K. & Basbaum, A. I. Anatomical and functional analysis of aquaporin 1, a water channel in primary afferent neurons. Pain 131, 8–20 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Hofman, P., Hoyng, P., vanderWerf, F., Vrensen, G. F. & Schlingemann, R. O. Lack of blood–brain barrier properties in microvessels of the prelaminar optic nerve head. Invest. Ophthalmol. Vis. Sci. 42, 895–901 (2001).

    CAS  PubMed  Google Scholar 

  49. Venero, J. L. et al. Detailed localization of aquaporin-4 messenger RNA in the CNS: preferential expression in periventricular organs. Neuroscience 94, 239–250 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Ma, T., Gao, H., Fang, X. & Yang, H. Water channel proteins in the peripheral nervous system in health and disease. Mol. Aspects Med. 33, 605–611 (2012).

    Article  PubMed  CAS  Google Scholar 

  51. Papadopoulos, M. C. & Verkman, A. S. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 11, 535–544 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jarius, S. & Wildemann, B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nature Rev. Neurol. 6, 383–392 (2010).

    Article  CAS  Google Scholar 

  53. Oshio, K., Watanabe, H., Yan, D., Verkman, A. S. & Manley, G. T. Impaired pain sensation in mice lacking Aquaporin-1 water channels. Biochem. Biophys. Res. Commun. 341, 1022–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Gao, H. et al. Localization of aquaporin-1 water channel in glial cells of the human peripheral nervous system. Glia 53, 783–787 (2006).

    Article  PubMed  Google Scholar 

  55. Nandasena, B. G. et al. Immunolocalization of aquaporin-1 in the mechanoreceptive Ruffini endings in the periodontal ligament. Brain Res. 1157, 32–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Li, J., Patil, R. V. & Verkman, A. S. Mildly abnormal retinal function in transgenic mice without Müller cell aquaporin-4 water channels. Invest. Ophthalmol. Vis. Sci. 43, 573–579 (2002).

    PubMed  Google Scholar 

  57. Lu, D. C., Zhang, H., Zador, Z. & Verkman, A. S. Impaired olfaction in mice lacking aquaporin-4 water channels. FASEB J. 22, 3216–3223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li, J. & Verkman, A. S. Impaired hearing in mice lacking aquaporin-4 water channels. J. Biol. Chem. 276, 31233–31237 (2001). This is the first report showing that AQP4 has a role in sensory perception.

    Article  CAS  PubMed  Google Scholar 

  59. Verkman, A. S., Ruiz-Ederra, J. & Levin, M. H. Functions of aquaporins in the eye. Prog. Retin. Eye Res. 27, 420–433 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nagahama, M., Ma, N., Semba, R. & Naruse, S. Aquaporin 1 immunoreactive enteric neurons in the rat ileum. Neurosci. Lett. 395, 206–210 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Arciszewski, M. B. Neurochemical properties of aquaporin 1-expressing sensory neurons from the ovine trigeminal ganglion. Anat. Histol. Embryol. 41, 184–189 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Thi, M. M., Spray, D. C. & Hanani, M. Aquaporin-4 water channels in enteric neurons. J. Neurosci. Res. 86, 448–456 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ishihara, E. et al. Neuropathological alteration of aquaporin 1 immunoreactive enteric neurons in the streptozotocin-induced diabetic rats. Auton. Neurosci. 138, 31–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Richardson, S. M., Knowles, R., Marples, D., Hoyland, J. A. & Mobasheri, A. Aquaporin expression in the human intervertebral disc. J. Mol. Histol. 39, 303–309 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Aharon, R. & Bar-Shavit, Z. Involvement of aquaporin 9 in osteoclast differentiation. J. Biol. Chem. 281, 19305–19309 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Bass, N. H., Hess, H. H., Pope, A. & Thalheimer, C. Quantitative cytoarchitectonic distribution of neurons, glia, and DNa in rat cerebral cortex. J. Comp. Neurol. 143, 481–490 (1971).

    Article  CAS  PubMed  Google Scholar 

  67. Arcienega, I. I., Brunet, J. F., Bloch, J. & Badaut, J. Cell locations for AQP1, AQP4 and 9 in the non-human primate brain. Neuroscience 167, 1103–1114 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Fischbarg, J. et al. Glucose transporters serve as water channels. Proc. Natl Acad. Sci. USA 87, 3244–3247 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Iwamoto, M. & Oiki, S. Counting ion and water molecules in a streaming file through the open-filter structure of the K channel. J. Neurosci. 31, 12180–12188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Papadopoulos, M. C. & Verkman, A. S. Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J. Biol. Chem. 280, 13906–13912 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Badaut, J. et al. Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J. Cereb. Blood Flow Metab. 31, 819–831 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Haj-Yasein, N. N. et al. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc. Natl Acad. Sci. USA 108, 17815–17820 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Marmarou, A. A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg. Focus 22, e1 (2007).

    PubMed  Google Scholar 

  74. Papadopoulos, M. C. & Verkman, A. S. Aquaporin-4 and brain edema. Pediatr. Nephrol. 22, 778–784 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zador, Z., Stiver, S., Wang, V. & Manley, G. T. Role of aquaporin-4 in cerebral edema and stroke. Handb Exp. Pharmacol. 190, 159–170 (2009).

    CAS  Google Scholar 

  76. Sun, M. C., Honey, C. R., Berk, C., Wong, N. L. & Tsui, J. K. Regulation of aquaporin-4 in a traumatic brain injury model in rats. J. Neurosurg. 98, 565–569 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Saadoun, S., Papadopoulos, M. C. & Krishna, S. Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review. J. Clin. Pathol. 56, 972–975 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Filippidis, A. S., Kalani, M. Y. & Rekate, H. L. Hydrocephalus and aquaporins: the role of aquaporin-4. Acta Neurochir. Suppl. 113, 55–58 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. 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). This study provides the first direct evidence that AQP4 plays a part in brain oedema.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Vajda, 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nico, B. et al. Severe alterations of endothelial and glial cells in the blood–brain barrier of dystrophic mdx mice. Glia 42, 235–251 (2003).

    Article  PubMed  Google Scholar 

  83. Saadoun, S., Bell, B. A., Verkman, A. S. & Papadopoulos, M. C. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain 131, 1087–1098 (2008).

    Article  PubMed  Google Scholar 

  84. Thrane, A. S. et al. Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc. Natl Acad. Sci. USA 108, 846–851 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Yang, B., Zador, Z. & Verkman, A. S. Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J. Biol. Chem. 283, 15280–15286 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bloch, O., Papadopoulos, M. C., Manley, G. T. & Verkman, A. S. Aquaporin-4 gene deletion in mice increases focal edema associated with staphylococcal brain abscess. J. Neurochem. 95, 254–262 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Tait, M. J., Saadoun, S., Bell, B. A., Verkman, A. S. & Papadopoulos, M. C. Increased brain edema in aqp4-null mice in an experimental model of subarachnoid hemorrhage. Neuroscience 167, 60–67 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Lee, D. J. et al. Aquaporin-4-dependent edema clearance following status epilepticus. Epilepsy Res. 98, 264–268 (2012).

    CAS  Google Scholar 

  89. Kimura, A. et al. Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann. Neurol. 67, 794–801 (2010).

    PubMed  Google Scholar 

  90. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl. Med 4, 147ra111 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Feng, X. et al. Sporadic obstructive hydrocephalus in Aqp4 null mice. J. Neurosci. Res. 87, 1150–1155 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bloch, O., Auguste, K. I., Manley, G. T. & Verkman, A. S. Accelerated progression of kaolin-induced hydrocephalus in aquaporin-4-deficient mice. J. Cereb. Blood Flow Metab. 26, 1527–1537 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Loitto, V. M. & Magnusson, K. E. Hg2+ and small-sized polyethylene glycols have inverse effects on membrane permeability, while both impair neutrophil cell motility. Biochem. Biophys. Res. Commun. 316, 370–378 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Saadoun, S., Papadopoulos, M. C., Hara-Chikuma, M. & Verkman, A. S. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434, 786–792 (2005). This study demonstrates that AQPs facilitate cell migration.

    Article  CAS  PubMed  Google Scholar 

  95. Papadopoulos, M. C., Saadoun, S. & Verkman, A. S. Aquaporins and cell migration. Pflugers Arch. 456, 693–700 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Hu, J. & Verkman, A. S. Increased migration and metastatic potential of tumor cells expressing aquaporin water channels. FASEB J. 20, 1892–1894 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Saadoun, S. et al. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J. Cell Sci. 118, 5691–5698 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Auguste, K. I. et al. Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. FASEB J. 21, 108–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Charras, G. T., Yarrow, J. C., Horton, M. A., Mahadevan, L. & Mitchison, T. J. Non-equilibration of hydrostatic pressure in blebbing cells. Nature 435, 365–369 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rabinovitch, M. & DeStefano, M. J. Spontaneous migration of normal human polymorphonuclear neutrophils under agarose: enhancement by media of lowered pH or osmolality. J. Reticuloendothel. Soc. 29, 329–339 (1981).

    CAS  PubMed  Google Scholar 

  101. Nicchia, G. P. et al. New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43. FASEB J. 19, 1674–1676 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Binder, D. K., Oshio, K., Ma, T., Verkman, A. S. & Manley, G. T. Increased seizure threshold in mice lacking aquaporin-4 water channels. Neuroreport 15, 259–262 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Lee, D. J., Hsu, M. S., Seldin, M. M., Arellano, J. L. & Binder, D. K. Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis. Exp. Neurol. 235, 246–255 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Binder, D. K., Nagelhus, E. A. & Ottersen, O. P. Aquaporin-4 and epilepsy. Glia 60, 1203–1214 (2012).

    Article  PubMed  Google Scholar 

  105. Strohschein, S. et al. Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia 59, 973–980 (2011).

    Article  PubMed  Google Scholar 

  106. Nicholson, C. & Sykova, E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 21, 207–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Ruiz-Ederra, J., Zhang, H. & Verkman, A. S. Evidence against functional interaction between aquaporin-4 water channels and Kir4.1 potassium channels in retinal Müller cells. J. Biol. Chem. 282, 21866–21872 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Jin, B. J., Zhang, B., Binder, D. K. & Verkman, A. S. Aquaporin-4-dependent K+ and water transport modeled in brain extracellular space following neuroexcitation. J. Gen. Physiol. 141, 261–272 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang, H. & Verkman, A. S. Aquaporin-1 tunes pain perception by interaction with Nav1.8 Na+ channels in dorsal root ganglion neurons. J. Biol. Chem. 285, 5896–5906 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Wingerchuk, D. M., Lennon, V. A., Lucchinetti, C. F., Pittock, S. J. & Weinshenker, B. G. The spectrum of neuromyelitis optica. Lancet Neurol. 6, 805–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Lennon, V. A. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S. & Hinson, S. R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 (2005). This study identifies AQP4 as the target of NMO autoantibodies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pisani, F. et al. Identification of two major conformational aquaporin-4 epitopes for neuromyelitis optica autoantibody binding. J. Biol. Chem. 286, 9216–9224 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tani, T. et al. Identification of binding sites for anti-aquaporin 4 antibodies in patients with neuromyelitis optica. J. Neuroimmunol. 211, 110–113 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Yu, X. et al. Identification of peptide targets in neuromyelitis optica. J. Neuroimmunol. 236, 65–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nicchia, G. P. et al. Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies. Glia 57, 1363–1373 (2009).

    Article  PubMed  Google Scholar 

  118. Hinson, S. R. et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc. Natl Acad. Sci. USA 109, 1245–1250 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Crane, J. M. et al. Binding affinity and specificity of neuromyelitis optica autoantibodies to aquaporin-4 M1/M23 isoforms and orthogonal arrays. J. Biol. Chem. 286, 16516–16524 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Phuan, P. W., Ratelade, J., Rossi, A., Tradtrantip, L. & Verkman, A. S. Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays. J. Biol. Chem. 287, 13829–13839 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ratelade, J., Bennett, J. L. & Verkman, A. S. Evidence against cellular internalization in vivo of NMO-IgG, aquaporin-4, and excitatory amino acid transporter 2 in neuromyelitis optica. J. Biol. Chem. 286, 45156–45164 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Saadoun, S. et al. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 133, 349–361 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Johnson, D. R. & O'Neill, B. P. Glioblastoma survival in the United States before and during the temozolomide era. J. Neurooncol. 107, 359–364 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Ikota, H., Kinjo, S., Yokoo, H. & Nakazato, Y. Systematic immunohistochemical profiling of 378 brain tumors with 37 antibodies using tissue microarray technology. Acta Neuropathol. 111, 475–482 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Warth, A. et al. Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood–brain barrier disturbance but not with patient survival. J. Neurosci. Res. 85, 1336–1346 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Badaut, J. Aquaglyceroporin 9 in brain pathologies. Neuroscience 168, 1047–1057 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Nico, B. et al. Aquaporin-4 contributes to the resolution of peritumoural brain oedema in human glioblastoma multiforme after combined chemotherapy and radiotherapy. Eur. J. Cancer 45, 3315–3325 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Verkman, A. S., Hara-Chikuma, M. & Papadopoulos, M. C. Aquaporins — new players in cancer biology. J. Mol. Med. 86, 523–529 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Frigeri, A., Nicchia, G. P. & Svelto, M. Aquaporins as targets for drug discovery. Curr. Pharm. Des. 13, 2421–2427 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Yool, A. J., Brown, E. A. & Flynn, G. A. Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer. Clin. Exp. Pharmacol. Physiol. 37, 403–409 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Niemietz, C. M. & Tyerman, S. D. New potent inhibitors of aquaporins: silver and gold compounds inhibit aquaporins of plant and human origin. FEBS Lett. 531, 443–447 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Huber, V. J., Tsujita, M., Kwee, I. L. & Nakada, T. Inhibition of aquaporin 4 by antiepileptic drugs. Bioorg. Med. Chem. 17, 418–424 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Huber, V. J., Tsujita, M., Yamazaki, M., Sakimura, K. & Nakada, T. Identification of arylsulfonamides as Aquaporin 4 inhibitors. Bioorg. Med. Chem. Lett. 17, 1270–1273 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Migliati, E. et al. Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site. Mol. Pharmacol. 76, 105–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ozu, M., Dorr, R. A., Teresa Politi, M., Parisi, M. & Toriano, R. Water flux through human aquaporin 1: inhibition by intracellular furosemide and maximal response with high osmotic gradients. Eur. Biophys. J. 40, 737–746 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Yukutake, Y., Hirano, Y., Suematsu, M. & Yasui, M. Rapid and reversible inhibition of aquaporin-4 by zinc. Biochemistry 48, 12059–12061 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Mola, M. G., Nicchia, G. P., Svelto, M., Spray, D. C. & Frigeri, A. Automated cell-based assay for screening of aquaporin inhibitors. Anal. Chem. 81, 8219–8229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yang, B., Zhang, H. & Verkman, A. S. Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. Bioorg. Med. Chem. 16, 7489–7493 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tradtrantip, L. et al. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann. Neurol. 71, 314–322 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tradtrantip, L. et al. Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. 26, 2197–2208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tradtrantip, L., Ratelade, J., Zhang, H. & Verkman, A. S. Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 IgG into therapeutic antibody. Ann. Neurol. 73, 77–85 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Matiello, M. et al. Genetic analysis of aquaporin-4 in neuromyelitis optica. Neurology 77, 1149–1155 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Kleffner, I. et al. The role of aquaporin-4 polymorphisms in the development of brain edema after middle cerebral artery occlusion. Stroke 39, 1333–1335 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Heuser, K. et al. Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy. Epilepsy Res. 88, 55–64 (2010).

    CAS  Google Scholar 

  145. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fan, Y. et al. Sex- and region-specific alterations of basal amino acid and monoamine metabolism in the brain of aquaporin-4 knockout mice. J. Neurosci. Res. 82, 458–464 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. Saadoun, S. et al. AQP4 gene deletion in mice does not alter blood-brain barrier integrity or brain morphology. Neuroscience 161, 764–772 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Binder, D. K., Papadopoulos, M. C., Haggie, P. M. & Verkman, A. S. In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J. Neurosci. 24, 8049–8056 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhang, H. & Verkman, A. S. Microfiberoptic measurement of extracellular space volume in brain and tumor slices based on fluorescent dye partitioning. Biophys. J. 99, 1284–1291 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Yao, X., Hrabetova, S., Nicholson, C. & Manley, G. T. Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J. Neurosci. 28, 5460–5464 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Eilert-Olsen, M. et al. Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia 60, 432–440 (2012).

    Article  PubMed  Google Scholar 

  152. Zeng, X. N. et al. Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. Mol. Cell. Neurosci. 34, 34–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Li, L., Zhang, H., Varrin-Doyer, M., Zamvil, S. S. & Verkman, A. S. Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J. 25, 1556–1566 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Skucas, V. A. et al. Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4. J. Neurosci. 31, 6392–6397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Benfenati, V. et al. An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes. Proc. Natl Acad. Sci. USA 108, 2563–2568 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Li, Z. et al. Aquaporin-4 knockout regulated cocaine-induced behavior and neurochemical changes in mice. Neurosci. Lett. 403, 294–298 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Fan, Y. et al. Aquaporin-4 promotes memory consolidation in Morris water maze. Brain Struct. Funct. 218, 39–50 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Yang, W. et al. Aquaporin-4 mediates astrocyte response to β-amyloid. Mol. Cell. Neurosci. 49, 406–414 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Amiry-Moghaddam, M. et al. Brain mitochondria contain aquaporin water channels: evidence for the expression of a short AQP9 isoform in the inner mitochondrial membrane. FASEB J. 19, 1459–1467 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Bennett, J. L. et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann. Neurol. 66, 617–629 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Our research is funded by the US National Institutes of Health and the Guthy-Jackson Charitable Foundation. We thank S. Saadoun for providing helpful criticism of the manuscript.

Author information

Authors and Affiliations

  1. Academic Neurosurgery Unit, St. George's, University of London, Tooting, SW17 0RE, London, UK

    Marios C. Papadopoulos

  2. Departments of Medicine and Physiology, University of California, San Francisco, 94143, California, USA

    Alan S. Verkman

Authors
  1. Marios C. Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan S. Verkman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marios C. Papadopoulos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

RCSB Protein Data Bank

3GD8

FURTHER INFORMATION

Alan S. Verkman's homepage

Glossary

α-syntrophin

An intracellular protein that may form a complex with aquaporin 4.

Agrin

A proteoglycan attached to extracellular matrix that may anchor aquaporin 4 in the membrane.

Glial-limiting membrane

This is the interface between the brain and the surrounding cerebrospinal fluid, and comprises astrocyte processes.

Circumventricular organs

These are regions of the brain near ventricles that lack the blood–brain barrier.

Choroid plexus

An intraventricular epithelial structure that secretes cerebrospinal fluid.

Tanycytes

These are elongated cells that project from the third ventricle to the hypothalamus.

Ruffini mechanoreceptors

These are skin mechanoreceptors.

Müller cells

These are aquaporin 4-expressing retinal glial cells.

Claudius cells

These are supporting cells (non-excitable cells) in the inner ear.

Hensen cells

These are supporting cells (non-excitable cells) in the inner ear.

Inner sulcus cells

These are supporting cells (non-excitable cells) in the inner ear.

Cytotoxic oedema

This is the intracellular accumulation of excess water (cell-swelling oedema).

Vasogenic oedema

This is the interstitial accumulation of excess brain water (leaky-vessel oedema).

Ependyma

A membrane of epithelial cells lining the ventricles.

Kaolin

This is aluminium silicate that causes obstructive hydrocephalus when injected into the cisterna magna of rodents.

Lamellipodia

Projections at the front end of a migrating cell.

Glioblastoma multiforme

This is a highly infiltrative, malignant tumour of astrocytes.

C5b–C9 complexes

Cell plasma membrane pores composed of the complement proteins C5b, C6, C7, C8 and C9. Deposition of enough pores causes cell lysis.

Plasma blast

Upon activation by T helper cells, B cells differentiate into plasma cells that secrete high levels of antibody. Plasma blasts are the most immature plasma cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Papadopoulos, M., Verkman, A. Aquaporin water channels in the nervous system. Nat Rev Neurosci 14, 265–277 (2013). https://doi.org/10.1038/nrn3468

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3468

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing