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Gene Review

AQP4  -  aquaporin 4

Homo sapiens

Synonyms: AQP-4, Aquaporin-4, HMIWC2, MIWC, Mercurial-insensitive water channel, ...
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Disease relevance of AQP4

  • The expression of AQP4 and AQP9 in astrocytes changes after brain ischemia or traumatic injury, and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions [1].
  • Immunoblot analysis of Sf9 cells infected with recombinant baculovirus showed greatest AQP4 expression at 72 h after infection at a multiplicity-of-infection of 5 [2].
  • Further insight into the mechanisms by which brain AQPs are regulated will be of utmost clinical importance, since perturbed water flow via brain AQPs has been implicated in many neurological diseases and since, in brain edema, water flow via AQP4 may have a harmful effect [3].
  • Using Western blot, the authors show that immunoreactivity for AQP4 is elevated in brain homogenates from the mid frontal gyrus of patients who died with HIVD (P < .005 HIV seronegative versus HIVD) [4].
  • We found that AQP4 completely covered the surface of the glioma cells. alpha-Dystroglycan was absent from glial membranes but retained in endothelial membranes [5].

Psychiatry related information on AQP4


High impact information on AQP4

  • Expression of AQP4 in transfected cells increased the osmotic water permeability coefficient (Pf) from 2.02 +/- 0.3 x 10-4 to 16.37 +/- 0.5 x 10-4 cm/s at 20 degrees C. Freeze-fracture EM showed distinct orthogonal arrays of particles (OAPs), the morphological signature of AQP4, on the plasma membrane of AQP4-expressing cells [9].
  • Cell surface biotinylation experiments confirmed that AQP4 is internalized after 20 min of histamine exposure, which may account for the downregulation of water transport [9].
  • This is the first evidence for short term rearrangement of OAPs in an established AQP4-expressing cell line [9].
  • AQP4 is also specifically expressed in the basolateral membranes of epithelial cells [10].
  • AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression [10].

Chemical compound and disease context of AQP4


Biological context of AQP4

  • Based on these findings, it was possible to convert AQP1 into a cotranslational biogenesis mode similar to that of AQP4 by substituting just two peptide regions at the N terminus of TM2 and the C terminus of TM3 [16].
  • Using oocytes, externally applied TEA blocked AQP1/AQP2/AQP4 with IC50 values of 1.4, 6.2, and 9.8 microM, respectively [17].
  • AQP1, AQP4, and AQP9 have been identified in the central nervous system and demonstrated or proposed to play important roles in brain water homeostasis [18].
  • Phosphorylation affects the gating of AQP4 and the trafficking and insertion into membrane of AQP1 [3].
  • Using a homologue cloning technique, we isolated two distinct qAQP4 cDNAs from quail medullary cones; long (L, open reading frames) and short (S) cDNA encoded 335 (qAQP4-L) and 301 (qAQP4-S) amino acids with, respectively, 80% and 87% identity to human long- and short-form AQP4. qAQP4-S is identical to qAQP4-L from the second initiation site [19].

Anatomical context of AQP4

  • AQP4 and AQP9, which are broadly expressed in astroglial cells in brain and spinal cord, were not localized in glial cells in the peripheral nerve plexuses [18].
  • Immunostaining and cell membrane fractionation indicated AQP4 plasma membrane expression [2].
  • AQP4 was detected in basolateral membranes in ciliated ducts and by in situ in gland acinar cells [20].
  • The presence of AQP4 and AQP9 in different subsets of ANSC-derived glial cells and in different cellular compartments suggests different roles of the two proteins in these cells, indicating that ANSC-derived astrocytes might maintain in vitro the heterogeneity that characterize the astrocyte-like cell populations in the SVZ in vivo [21].
  • The alveolar epithelium has all three AQPs represented, with AQP5 and AQP4 localized to type I pneumocytes and AQP3 to type II cells [20].

Associations of AQP4 with chemical compounds

  • AQP3 resides in the basolateral membranes of collecting duct principal cells providing an exit pathway for water, and AQP4 is abundant in brain, where it apparently functions as the hypothalamic osmoreceptor responsible for secretion of antidiuretic hormone [22].
  • Osmotic water permeability (Pf) in plasma membrane vesicles from AQP4-expressing Sf9 cells was very high (0.053 cm/s at 10 degrees C), weakly temperature dependent (activation energy, 4.5 kcal/mol), and not inhibited by HgCl2 [2].
  • Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human AQP4-expressing gastric cells [9].
  • We provide strong evidence that reactive microglial cells highly express AQP4 mRNA and protein in response to LPS injections [23].
  • We have cloned three kidney cDNAs with homology to the water channel (aquaporin) family, including a mercurial-insensitive water channel (MIWC), and a glycerol-transporting protein (GLIP) in collecting duct basolateral membrane [24].

Co-localisations of AQP4


Regulatory relationships of AQP4

  • Anatomically AQP4 was more highly expressed in all categories of MS tissue compared to normal control tissues with the most abundant expression in active lesions [26].
  • In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain [27].
  • There was no difference in AQP4 protein levels between DEX group and control group at the two above-mentioned brain regions at day 1 after ICH [15].

Other interactions of AQP4

  • Two aquaporins have been identified so far in the CNS, AQP1 and AQP4 [28].
  • Cells transfected with human AQP4 and AQP5, which are also expressed in airway epithelia, were insensitive to nickel and extracellular acidification [29].
  • Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny [21].
  • The assembly between AQP4 and syntrophin is required for the proper localization of AQP4 in the astrocyte plasma membrane that faces capillaries [3].
  • The myofiber surface immunostaining with anti-AQP4 antibody in muscles with neurogenic atrophy was reduced on the surface of scattered myofibers, small angulated myofibers, and myofibers in small- and large-group atrophy despite the presence of dystrophin [30].

Analytical, diagnostic and therapeutic context of AQP4


  1. Hyperosmolar mannitol simulates expression of aquaporins 4 and 9 through a p38 mitogen-activated protein kinase-dependent pathway in rat astrocytes. Arima, H., Yamamoto, N., Sobue, K., Umenishi, F., Tada, T., Katsuya, H., Asai, K. J. Biol. Chem. (2003) [Pubmed]
  2. Very high single channel water permeability of aquaporin-4 in baculovirus-infected insect cells and liposomes reconstituted with purified aquaporin-4. Yang, B., van Hoek, A.N., Verkman, A.S. Biochemistry (1997) [Pubmed]
  3. Regulation of brain aquaporins. Gunnarson, E., Zelenina, M., Aperia, A. Neuroscience (2004) [Pubmed]
  4. Aquaporin 4 is increased in association with human immunodeficiency virus dementia: implications for disease pathogenesis. St Hillaire, C., Vargas, D., Pardo, C.A., Gincel, D., Mann, J., Rothstein, J.D., McArthur, J.C., Conant, K. J. Neurovirol. (2005) [Pubmed]
  5. Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Warth, A., Kröger, S., Wolburg, H. Acta Neuropathol. (2004) [Pubmed]
  6. Increased expression of water channel aquaporin 1 and aquaporin 4 in Creutzfeldt-Jakob disease and in bovine spongiform encephalopathy-infected bovine-PrP transgenic mice. Rodr??guez, A., P??rez-Gracia, E., Espinosa, J.C., Pumarola, M., Torres, J.M., Ferrer, I. Acta Neuropathol. (2006) [Pubmed]
  7. The human AQP4 gene: definition of the locus encoding two water channel polypeptides in brain. Lu, M., Lee, M.D., Smith, B.L., Jung, J.S., Agre, P., Verdijk, M.A., Merkx, G., Rijss, J.P., Deen, P.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. Implications of the aquaporin-4 structure on array formation and cell adhesion. Hiroaki, Y., Tani, K., Kamegawa, A., Gyobu, N., Nishikawa, K., Suzuki, H., Walz, T., Sasaki, S., Mitsuoka, K., Kimura, K., Mizoguchi, A., Fujiyoshi, Y. J. Mol. Biol. (2006) [Pubmed]
  9. Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human AQP4-expressing gastric cells. Carmosino, M., Procino, G., Nicchia, G.P., Mannucci, R., Verbavatz, J.M., Gobin, R., Svelto, M., Valenti, G. J. Cell Biol. (2001) [Pubmed]
  10. Polarized trafficking and surface expression of the AQP4 water channel are coordinated by serial and regulated interactions with different clathrin-adaptor complexes. Madrid, R., Le Maout, S., Barrault, M.B., Janvier, K., Benichou, S., Mérot, J. EMBO J. (2001) [Pubmed]
  11. Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. Zeng, X.N., Sun, X.L., Gao, L., Fan, Y., Ding, J.H., Hu, G. Mol. Cell. Neurosci. (2007) [Pubmed]
  12. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Guo, Q., Sayeed, I., Baronne, L.M., Hoffman, S.W., Guennoun, R., Stein, D.G. Exp. Neurol. (2006) [Pubmed]
  13. Bench to bedside: brain edema and cerebral resuscitation: the present and future. Xiao, F. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. (2002) [Pubmed]
  14. Modulation of AQP4 expression by the protein kinase C activator, phorbol myristate acetate, decreases ischemia-induced brain edema. Kleindienst, A., Fazzina, G., Amorini, A.M., Dunbar, J.G., Glisson, R., Marmarou, A. Acta Neurochir. Suppl. (2006) [Pubmed]
  15. Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats. Gu, Y.T., Zhang, H., Xue, Y.X. Neurosci. Lett. (2007) [Pubmed]
  16. Identification of sequence determinants that direct different intracellular folding pathways for aquaporin-1 and aquaporin-4. Foster, W., Helm, A., Turnbull, I., Gulati, H., Yang, B., Verkman, A.S., Skach, W.R. J. Biol. Chem. (2000) [Pubmed]
  17. Quaternary ammonium compounds as water channel blockers. Specificity, potency, and site of action. Detmers, F.J., de Groot, B.L., Müller, E.M., Hinton, A., Konings, I.B., Sze, M., Flitsch, S.L., Grubmüller, H., Deen, P.M. J. Biol. Chem. (2006) [Pubmed]
  18. Localization of aquaporin-1 water channel in glial cells of the human peripheral nervous system. Gao, H., He, C., Fang, X., Hou, X., Feng, X., Yang, H., Zhao, X., Ma, T. Glia (2006) [Pubmed]
  19. Two distinct aquaporin-4 cDNAs isolated from medullary cone of quail kidney. Yang, Y., Cui, Y., Fan, Z., Cook, G.A., Nishimura, H. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. (2007) [Pubmed]
  20. Expression and localization of epithelial aquaporins in the adult human lung. Kreda, S.M., Gynn, M.C., Fenstermacher, D.A., Boucher, R.C., Gabriel, S.E. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  21. Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny. Cavazzin, C., Ferrari, D., Facchetti, F., Russignan, A., Vescovi, A.L., La Porta, C.A., Gritti, A. Glia (2006) [Pubmed]
  22. The aquaporin family of water channels in kidney. Nielsen, S., Agre, P. Kidney Int. (1995) [Pubmed]
  23. In vivo expression of aquaporin-4 by reactive microglia. Tomás-Camardiel, M., Venero, J.L., de Pablos, R.M., Rite, I., Machado, A., Cano, J. J. Neurochem. (2004) [Pubmed]
  24. Structure and function of kidney water channels. Verkman, A.S., Shi, L.B., Frigeri, A., Hasegawa, H., Farinas, J., Mitra, A., Skach, W., Brown, D., Van Hoek, A.N., Ma, T. Kidney Int. (1995) [Pubmed]
  25. Potassium channels of glial cells: distribution and function. Horio, Y. Jpn. J. Pharmacol. (2001) [Pubmed]
  26. Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Sinclair, C., Kirk, J., Herron, B., Fitzgerald, U., McQuaid, S. Acta Neuropathol. (2007) [Pubmed]
  27. Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review. Saadoun, S., Papadopoulos, M.C., Krishna, S. J. Clin. Pathol. (2003) [Pubmed]
  28. Aquaporins in the central nervous system. Venero, J.L., Vizuete, M.L., Machado, A., Cano, J. Prog. Neurobiol. (2001) [Pubmed]
  29. Nickel and extracellular acidification inhibit the water permeability of human aquaporin-3 in lung epithelial cells. Zelenina, M., Bondar, A.A., Zelenin, S., Aperia, A. J. Biol. Chem. (2003) [Pubmed]
  30. Reduced expression of aquaporin 4 in human muscles with amyotrophic lateral sclerosis and other neurogenic atrophies. Jimi, T., Wakayama, Y., Matsuzaki, Y., Hara, H., Inoue, M., Shibuya, S. Pathol. Res. Pract. (2004) [Pubmed]
  31. Altered expression of aquaporins in bullous keratopathy and Fuchs' dystrophy corneas. Kenney, M.C., Atilano, S.R., Zorapapel, N., Holguin, B., Gaster, R.N., Ljubimov, A.V. J. Histochem. Cytochem. (2004) [Pubmed]
  32. Diversity of aquaporin mRNA expressed by rat and human retinas. Tenckhoff, S., Hollborn, M., Kohen, L., Wolf, S., Wiedemann, P., Bringmann, A. Neuroreport (2005) [Pubmed]
  33. A water channel closely related to rat brain aquaporin 4 is expressed in acid- and pepsinogen-secretory cells of human stomach. Misaka, T., Abe, K., Iwabuchi, K., Kusakabe, Y., Ichinose, M., Miki, K., Emori, Y., Arai, S. FEBS Lett. (1996) [Pubmed]
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