Key Points
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Aquaporins (AQPs) are water channel proteins that are expressed in the plasma membranes of cells. They are involved in many physiological functions, including renal water balance, epithelial fluid secretion, cell migration, brain oedema and metabolism in adipocytes.
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Aquaporinopathies include nephrogenic diabetes insipidus (which is caused by a loss-of-function mutation in AQP2) and neuromyelitis optica (which is caused by the development of AQP4-targeted autoantibodies).
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Modulators of AQP function are predicted to have broad clinical indications in oedema, cancer, obesity, brain injury, glaucoma, epilepsy and inflammation.
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The identification of useful small-molecule AQP inhibitors has been slow, in part because of technical challenges in assaying the water-transporting function of AQPs and challenges associated with targeting the compact, pore-containing AQP molecule.
Abstract
The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators.
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References
Fu, D. & Lu, M. The structural basis of water permeation and proton exclusion in aquaporins. Mol. Membr. Biol. 24, 366–374 (2007).
Gonen, T. & Walz, T. The structure of aquaporins. Q. Rev. Biophys. 39, 361–396 (2006).
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).
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).
Smith, A. J., Jin, B. J., Ratelade, J. & Verkman, A. S. Aggregation state determines the localization and function of M1– and M23–aquaporin-4 in astrocytes. J. Cell. Biol. 204, 559–573 (2014). This study shows the dual functions of AQP4 isoforms and arrays.
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).
Murata, K. et al. Structural determinants of water permeation through aquaporin-1. Nature 407, 599–605 (2000).
Fu, D. et al. Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290, 481–486 (2000).
Beitz, E., Wu, B., Holm, L. M., Schultz, J. E. & Zeuthen, T. Point mutations in the aromatic/arginine region in aquaporin 1 allow passage of urea, glycerol, ammonia, and protons. Proc. Natl Acad. Sci. USA 103, 269–274 (2006).
Ho, J. D. et al. Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance. Proc. Natl Acad. Sci. USA 106, 7437–7442 (2009). This paper describes the high-resolution crystal structure of AQP4.
de Groot, B. L. & Grubmuller, H. The dynamics and energetics of water permeation and proton exclusion in aquaporins. Curr. Opin. Struct. Biol. 15, 176–183 (2005).
Burykin, A. & Warshel, A. What really prevents proton transport through aquaporin? Charge self-energy versus proton wire proposals. Biophys. J. 85, 3696–3706 (2003).
Kato, M., Pisliakov, A. V. & Warshel, A. The barrier for proton transport in aquaporins as a challenge for electrostatic models: the role of protein relaxation in mutational calculations. Proteins 64, 829–844 (2006).
Chen, H., Wu, Y. & Voth, G. A. Origins of proton transport behavior from selectivity domain mutations of the aquaporin-1 channel. Biophys. J. 90, L73–L75 (2006).
Zhang, Y. B. & Chen, L. Y. In silico study of aquaporin V: effects and affinity of the central pore-occluding lipid. Biophys. Chem. 171, 24–30 (2013).
Janosi, L. & Ceccarelli, M. The gating mechanism of the human aquaporin 5 revealed by molecular dynamics simulations. PLoS ONE 8, e59897 (2013).
Tornroth-Horsefield, S., Hedfalk, K., Fischer, G., Lindkvist-Petersson, K. & Neutze, R. Structural insights into eukaryotic aquaporin regulation. FEBS Lett. 584, 2580–2588 (2010).
Fischer, G. et al. Crystal structure of a yeast aquaporin at 1.15 Å reveals a novel gating mechanism. PLoS Biol. 7, e1000130 (2009).
Ozu, M., Dorr, R. A., Gutierrez, F., Politi, M. T. & Toriano, R. Human AQP1 is a constitutively open channel that closes by a membrane-tension-mediated mechanism. Biophys. J. 104, 85–95 (2013).
Soveral, G., Macey, R. I. & Moura, T. F. Membrane stress causes inhibition of water channels in brush border membrane vesicles from kidney proximal tubule. Biol. Cell 89, 275–282 (1997).
Soveral, G., Madeira, A., Loureiro-Dias, M. C. & Moura, T. F. Membrane tension regulates water transport in yeast. Biochim. Biophys. Acta 1778, 2573–2579 (2008).
Bienert, G. P. et al. Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes. J. Biol. Chem. 282, 1183–1192 (2007).
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. 2009, 57–76 (2009).
Musa-Aziz, R., Chen, L. M., Pelletier, M. F. & Boron, W. F. Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG. Proc. Natl Acad. Sci. USA 106, 5406–5411 (2009).
Holm, L. M. et al. NH3 and NH4+ permeability in aquaporin-expressing Xenopus oocytes. Pflugers Arch. 450, 415–428 (2005).
Herrera, M., Hong, N. J. & Garvin, J. L. Aquaporin-1 transports NO across cell membranes. Hypertension 48, 157–164 (2006).
Wang, Y. & Tajkhorshid, E. Nitric oxide conduction by the brain aquaporin AQP4. Proteins 78, 661–670 (2010).
Tsukaguchi, H., Weremowicz, S., Morton, C. C. & Hediger, M. A. Functional and molecular characterization of the human neutral solute channel aquaporin-9. Am. J. Physiol. 277, F685–F696 (1999).
Hara-Chikuma, M. et al. Chemokine-dependent T cell migration requires aquaporin-3-mediated hydrogen peroxide uptake. J. Exp. Med. 209, 1743–1752 (2012).
Miller, E. W., Dickinson, B. C. & Chang, C. J. Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. Proc. Natl Acad. Sci. USA 107, 15681–15686 (2010).
Yool, A. J. & Weinstein, A. M. New roles for old holes: ion channel function in aquaporin-1. News Physiol. Sci. 17, 68–72 (2002).
Ma, T. et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J. Biol. Chem. 273, 4296–4299 (1998).
Schnermann, J. et al. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc. Natl Acad. Sci. USA 95, 9660–9664 (1998).
Chou, C. L. et al. Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaporin-1 null mice. J. Clin. Invest. 103, 491–496 (1999).
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).
Sasaki, S. Aquaporin 2: from its discovery to molecular structure and medical implications. Mol. Aspects Med. 33, 535–546 (2012).
Ma, T. et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc. Natl Acad. Sci. USA 97, 4386–4391 (2000).
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).
Yang, B., Gillespie, A., Carlson, E. J., Epstein, C. J. & Verkman, A. S. Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J. Biol. Chem. 276, 2775–2779 (2001).
Yang, B., Zhao, D. & Verkman, A. S. Hsp90 inhibitor partially corrects nephrogenic diabetes insipidus in a conditional knock-in mouse model of aquaporin-2 mutation. FASEB J. 23, 503–512 (2009).
Morishita, Y. et al. Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule. Mol. Cell. Biol. 25, 7770–7779 (2005).
Ma, T. et al. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J. Biol. Chem. 274, 20071–20074 (1999).
Song, Y. & Verkman, A. S. Aquaporin-5 dependent fluid secretion in airway submucosal glands. J. Biol. Chem. 276, 41288–41292 (2001).
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).
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).
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).
Papadopoulos, M. C. & Verkman, A. S. Potential utility of aquaporin modulators for therapy of brain disorders. Prog. Brain Res. 170, 589–601 (2008).
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 has a role in the development of brain oedema.
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).
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).
Katada, R. et al. Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia. FASEB J. 28, 705–714 (2013).
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).
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).
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).
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).
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).
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).
Kimura, A. et al. Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann. Neurol. 67, 794–801 (2010).
Binder, D. K. et al. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53, 631–636 (2006).
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).
Amiry-Moghaddam, M. et al. Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc. Natl Acad. Sci. USA 100, 13615–13620 (2003).
Jin, B. J., Zhang, H., Binder, D. K. & Verkman, A. S. Aquaporin-4-dependent K+ and water transport modeled in brain extracellular space following neuroexcitation. J. Gen. Physiol. 141, 119–132 (2013).
Saadoun, S. et al. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J. Cell Sci. 118, 5691–5698 (2005).
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).
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).
Oshio, K. et al. Expression of aquaporin water channels in mouse spinal cord. Neuroscience 127, 685–693 (2004).
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).
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).
Endo, M., Jain, R. K., Witwer, B. & Brown, D. Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas. Microvasc. Res. 58, 89–98 (1999).
Verkman, A. S., Hara-Chikuma, M. & Papadopoulos, M. C. Aquaporins — new players in cancer biology. J. Mol. Med. 86, 523–529 (2008).
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).
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 that AQP expression is increased in human tumours.
Warth, A., Kroger, S. & Wolburg, H. Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol. 107, 311–318 (2004).
Warth, A., Mittelbronn, M., Hulper, P., Erdlenbruch, B. & Wolburg, H. Expression of the water channel protein aquaporin-9 in malignant brain tumors. Appl. Immunohistochem Mol. Morphol. 15, 193–198 (2007).
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.
Esteva-Font, C., Jin, B. J. & Verkman, A. S. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. FASEB J. http://dx.doi.org/10.1096/fj.13-245621 (2013).
Hu, J. & Verkman, A. S. Increased migration and metastatic potential of tumor cells expressing aquaporin water channels. FASEB J. 20, 1892–1894 (2006).
Papadopoulos, M. C., Saadoun, S. & Verkman, A. S. Aquaporins and cell migration. Pflugers Arch. 456, 693–700 (2008).
Hara-Chikuma, M. & Verkman, A. S. Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption. Mol. Cell. Biol. 28, 326–332 (2008).
Zhang, Z. et al. Expression of aquaporin 5 increases proliferation and metastasis potential of lung cancer. J. Pathol. 221, 210–220 (2010).
Jung, H. J., Park, J. Y., Jeon, H. S. & Kwon, T. H. Aquaporin-5: a marker protein for proliferation and migration of human breast cancer cells. PLoS ONE 6, e28492 (2011).
Di Giusto, G. et al. Aquaporin 2-increased renal cell proliferation is associated with cell volume regulation. J. Cell Biochem. 113, 3721–3729 (2012).
Huang, Y. H. et al. Aquaporin 5 promotes the proliferation and migration of human gastric carcinoma cells. Tumour Biol. 34, 1743–1751 (2013).
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).
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).
Dumas, M. et al. Hydrating skin by stimulating biosynthesis of aquaporins. J. Drugs Dermatol. 6, s20–s24 (2007).
Verkman, A. S. A cautionary note on cosmetics containing ingredients that increase aquaporin-3 expression. Exp. Dermatol. 17, 871–872 (2008).
Levin, M. H. & Verkman, A. S. Aquaporin-3-dependent cell migration and proliferation during corneal re-epithelialization. Invest. Ophthalmol. Vis. Sci. 47, 4365–4372 (2006).
Hara-Chikuma, M. & Verkman, A. S. Aquaporin-3 facilitates epidermal cell migration and proliferation during wound healing. J. Mol. Med. 86, 221–231 (2008).
Chepelinsky, A. B. Structural function of MIP/aquaporin 0 in the eye lens; genetic defects lead to congenital inherited cataracts. Handb. Exp. Pharmacol. 2009, 265–297 (2009).
Zhu, N. et al. Defective macrophage function in aquaporin-3 deficiency. FASEB J. 25, 4233–4239 (2011).
Hara-Chikuma, M. et al. Progressive adipocyte hypertrophy in aquaporin-7-deficient mice: adipocyte glycerol permeability as a novel regulator of fat accumulation. J. Biol. Chem. 280, 15493–15496 (2005).
Hibuse, T. et al. Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. Proc. Natl Acad. Sci. USA 102, 10993–10998 (2005).
Marrades, M. P., Milagro, F. I., Martinez, J. A. & Moreno-Aliaga, M. J. Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers. Biochem. Biophys. Res. Commun. 339, 785–789 (2006).
Maeda, N., Hibuse, T. & Funahashi, T. Role of aquaporin-7 and aquaporin-9 in glycerol metabolism; involvement in obesity. Handb. Exp. Pharmacol. 2009, 233–249 (2009).
Jelen, S. et al. Aquaporin-9 and urea transporter-A gene deletions affect urea transmembrane passage in murine hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G1279–G1287 (2012).
Jelen, S. et al. Aquaporin-9 protein is the primary route of hepatocyte glycerol uptake for glycerol gluconeogenesis in mice. J. Biol. Chem. 286, 44319–44325 (2011).
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).
Liu, J., Xu, J., Gu, S., Nicholson, B. J. & Jiang, J. X. Aquaporin 0 enhances gap junction coupling via its cell adhesion function and interaction with connexin 50. J. Cell Sci. 124, 198–206 (2011).
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).
Deen, P. M. et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264, 92–95 (1994). This paper shows that mutations in human AQP2 cause defective urinary concentration in NDI.
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).
Goubau, C. et al. Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect. Genet. Med. 15, 55–63 (2013).
Blaydon, D. C. et al. Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am. J. Hum. Genet. 93, 330–335 (2013).
Cao, X. et al. Mutation in AQP5, encoding aquaporin 5, causes palmoplantar keratoderma Bothnia type. J. Invest. Dermatol. 134, 284–287 (2014).
Zhang, B., Jiang, Y., Yang, Y., Peng, F. & Hu, X. Correlation between serum thyroxine and complements in patients with multiple sclerosis and neuromyelitis optica. Neuro Endocrinol. Lett. 29, 256–260 (2008).
Edelman, J. L. & Miller, S. S. Epinephrine stimulates fluid absorption across bovine retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 32, 3033–3040 (1991).
Farinas, J., Kneen, M., Moore, M. & Verkman, A. S. Plasma membrane water permeability of cultured cells and epithelia measured by light microscopy with spatial filtering. J. Gen. Physiol. 110, 283–296 (1997).
Farinas, J. & Verkman, A. S. Cell volume and plasma membrane osmotic water permeability in epithelial cell layers measured by interferometry. Biophys. J. 71, 3511–3522 (1996).
Farinas, J., Simanek, V. & Verkman, A. S. Cell volume measured by total internal reflection microfluorimetry: application to water and solute transport in cells transfected with water channel homologs. Biophys. J. 68, 1613–1620 (1995).
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).
Galietta, L. J., Haggie, P. M. & Verkman, A. S. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220–224 (2001).
Baumgart, F., Rossi, A. & Verkman, A. S. Light inactivation of water transport and protein-protein interactions of aquaporin-Killer Red chimeras. J. Gen. Physiol. 139, 83–91 (2012).
Esteva-Font, C., Phuan, P. W., Anderson, M. O. & Verkman, A. S. A small molecule screen identifies selective inhibitors of urea transporter UT-A. Chem. Biol. 20, 1235–1244 (2013).
Levin, M. H., de la Fuente, R. & Verkman, A. S. Urearetics: a small molecule screen yields nanomolar potency inhibitors of urea transporter UT-B. FASEB J. 21, 551–563 (2007).
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 (2012).
Yang, B., van Hoek, A. N. & Verkman, A. S. Very high single channel water permeability of aquaporin-4 in baculovirus-infected insect cells and liposomes reconstituted with purified aquaporin-4. Biochemistry 36, 7625–7632 (1997).
Zhang, R. B., Logee, K. A. & Verkman, A. S. Expression of mRNA coding for kidney and red cell water channels in Xenopus oocytes. J. Biol. Chem. 265, 15375–15378 (1990).
Zeuthen, T., Zeuthen, E. & Macaulay, N. Water transport by GLUT2 expressed in Xenopus laevis oocytes. J. Physiol. 579, 345–361 (2007).
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).
Macey, R. I. & Farmer, R. E. Inhibition of water and solute permeability in human red cells. Biochim. Biophys. Acta 211, 104–106 (1970).
Zhang, R., van Hoek, A. N., Biwersi, J. & Verkman, A. S. A point mutation at cysteine 189 blocks the water permeability of rat kidney water channel CHIP28k. Biochemistry 32, 2938–2941 (1993).
Preston, G. M., Jung, J. S., Guggino, W. B. & Agre, P. The mercury-sensitive residue at cysteine 189 in the CHIP28 water channel. J. Biol. Chem. 268, 17–20 (1993).
Hasegawa, H., Ma, T., Skach, W., Matthay, M. A. & Verkman, A. S. Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J. Biol. Chem. 269, 5497–5500 (1994).
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).
Martins, A. P. et al. Aquaporin inhibition by gold(III) compounds: new insights. ChemMedChem 8, 1086–1092 (2013).
Martins, A. P. et al. Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound. PLoS ONE 7, e37435 (2012).
Bertrand, B. & Casini, A. A golden future in medicinal inorganic chemistry: the promise of anticancer gold organometallic compounds. Dalton Trans. 43, 4209–4219 (2014).
Nagy, E. M., Ronconi, L., Nardon, C. & Fregona, D. Noble metal-dithiocarbamates precious allies in the fight against cancer. Mini Rev. Med. Chem. 12, 1216–1229 (2012).
Bergamo, A. & Sava, G. Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs. Dalton Trans. 40, 7817–7823 (2011).
Brooks, H. L., Regan, J. W. & Yool, A. J. Inhibition of aquaporin-1 water permeability by tetraethylammonium: involvement of the loop E pore region. Mol. Pharmacol. 57, 1021–1026 (2000).
Detmers, F. J. et al. Quaternary ammonium compounds as water channel blockers. Specificity, potency, and site of action. J. Biol. Chem. 281, 14207–14214 (2006).
Ma, B. et al. Effects of acetazolamide and anordiol on osmotic water permeability in AQP1-cRNA injected Xenopus oocyte. Acta Pharmacol. Sin. 25, 90–97 (2004).
Gao, J. et al. Acetazolamide inhibits osmotic water permeability by interaction with aquaporin-1. Anal. Biochem. 350, 165–170 (2006).
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).
Huber, V. J., Tsujita, M., Kwee, I. L. & Nakada, T. Inhibition of aquaporin 4 by antiepileptic drugs. Bioorg. Med. Chem. 17, 418–424 (2009).
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).
Yool, A. J. et al. AqF026 is a pharmacologic agonist of the water channel aquaporin-1. J. Am. Soc. Nephrol. 24, 1045–1052 (2013).
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).
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).
Nicchia, G. P. et al. Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies. Glia 57, 1363–1373 (2009).
Seeliger, D. et al. Discovery of novel human aquaporin-1 blockers. ACS Chem. Biol. 8, 249–256 (2013).
Irwin, J. J. & Shoichet, B. K. ZINC — a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 45, 177–182 (2005).
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).
Wacker, S. J. et al. The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site. Mol. Membr. Biol. 30, 246–260 (2013).
Baum, B. J. et al. Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. Biochim. Biophys. Acta 1758, 1071–1077 (2006).
Gao, R. et al. AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. Gene Ther. 18, 38–42 (2011).
Baum, B. J. et al. Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction. Proc. Natl Acad. Sci. USA 109, 19403–19407 (2012).
Lennon, V. A. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 (2004).
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 is the first report showing that AQP4 is the target of autoantibodies produced in NMO.
Hinson, S. R. et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 69, 2221–2231 (2007).
Papadopoulos, M. C. & Verkman, A. S. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 11, 535–544 (2012).
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).
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).
Palace, J., Leite, M. I. & Jacob, A. A practical guide to the treatment of neuromyelitis optica. Pract. Neurol. 12, 209–214 (2012).
Tradtrantip, L. et al. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann. Neurol. 71, 314–322 (2012). This paper describes a monoclonal antibody therapy for NMO, involving a mutated, non-pathogenic blocking antibody.
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).
Tradtrantip, L., Ratelade, J., Zhang, H. & Verkman, A. S. Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann. Neurol. 73, 77–85 (2013).
Tradtrantip, L., Asavapanumas, N. & Verkman, A. S. Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase. Mol. Pharmacol. 83, 1268–1275 (2013).
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).
Chihara, N. et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc. Natl Acad. Sci. USA 108, 3701–3706 (2011).
Kieseier, B. C. et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol. 70, 390–393 (2013).
Araki, M. et al. Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod. Rheumatol 23, 827–831 (2013).
Bichet, D. G. Hereditary polyuric disorders: new concepts and differential diagnosis. Semin. Nephrol. 26, 224–233 (2006).
Wesche, D., Deen, P. M. & Knoers, N. V. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr. Nephrol. 27, 2183–2204 (2012).
Morello, J. P. et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J. Clin. Invest. 105, 887–895 (2000).
Olesen, E. T., Rutzler, M. R., Moeller, H. B., Praetorius, H. A. & Fenton, R. A. Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus. Proc. Natl Acad. Sci. USA 108, 12949–12954 (2011).
Tamarappoo, B. K. & Verkman, A. S. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J. Clin. Invest. 101, 2257–2267 (1998).
Soupene, E., King, N., Lee, H. & Kustu, S. Aquaporin Z of Escherichia coli: reassessment of its regulation and physiological role. J. Bacteriol. 184, 4304–4307 (2002).
Maurel, C., Reizer, J., Schroeder, J. I., Chrispeels, M. J. & Saier, M. H. Jr. Functional characterization of the Escherichia coli glycerol facilitator, GlpF, in Xenopus oocytes. J. Biol. Chem. 269, 11869–11872 (1994).
Kun, J. F. & de Carvalho, E. G. Novel therapeutic targets in Plasmodium falciparum: aquaglyceroporins. Expert Opin. Ther. Targets 13, 385–394 (2009).
Miranda, K. et al. Characterization of a novel organelle in Toxoplasma gondii with similar composition and function to the plant vacuole. Mol. Microbiol. 76, 1358–1375 (2010).
Li, Z. H. et al. Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi. J. Biol. Chem. 286, 43959–43971 (2011).
Bassarak, B., Uzcategui, N. L., Schonfeld, C. & Duszenko, M. Functional characterization of three aquaglyceroporins from Trypanosoma brucei in osmoregulation and glycerol transport. Cell Physiol. Biochem. 27, 411–420 (2011).
Castro-Borges, W. et al. Abundance of tegument surface proteins in the human blood fluke Schistosoma mansoni determined by QconCAT proteomics. J. Proteom. 74, 1519–1533 (2011).
Pavlovic-Djuranovic, S., Kun, J. F., Schultz, J. E. & Beitz, E. Dihydroxyacetone and methylglyoxal as permeants of the Plasmodium aquaglyceroporin inhibit parasite proliferation. Biochim. Biophys. Acta 1758, 1012–1017 (2006).
Liu, Y. et al. Aquaporin 9 is the major pathway for glycerol uptake by mouse erythrocytes, with implications for malarial virulence. Proc. Natl Acad. Sci. USA 104, 12560–12564 (2007).
Lindahl, E. & Sansom, M. S. Membrane proteins: molecular dynamics simulations. Curr. Opin. Struct. Biol. 18, 425–431 (2008).
Muller, E. M., Hub, J. S., Grubmuller, H. & de Groot, B. L. Is TEA an inhibitor for human aquaporin-1? Pflugers Arch. 456, 663–669 (2008).
Roudier, N., Verbavatz, J. M., Maurel, C., Ripoche, P. & Tacnet, F. Evidence for the presence of aquaporin-3 in human red blood cells. J. Biol. Chem. 273, 8407–8412 (1998).
Thiagarajah, J. R., Zhao, D. & Verkman, A. S. Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis. Gut 56, 1529–1535 (2007).
Li, J., Patil, R. V. & Verkman, A. S. Mildly abnormal retinal function in transgenic mice without Muller cell aquaporin-4 water channels. Invest. Ophthalmol. Vis. Sci. 43, 573–579 (2002).
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).
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, C1549–1561 (1997).
Saadoun, S. et al. Neuromyelitis optica IgG causes placental inflammation and fetal death. J. Immunol. 191, 2999–3005 (2013).
Li, J. & Verkman, A. S. Impaired hearing in mice lacking aquaporin-4 water channels. J. Biol. Chem. 276, 31233–31237 (2001).
Yang, B. et al. Skeletal muscle function and water permeability in aquaporin-4 deficient mice. Am. J. Physiol. Cell Physiol. 278, C1108–C1115 (2000).
Song, Y., Sonawane, N. & Verkman, A. S. Localization of aquaporin-5 in sweat glands and functional analysis using knockout mice. J. Physiol. 541, 561–568 (2002).
Kwon, T. H. et al. Physiology and pathophysiology of renal aquaporins. Semin. Nephrol. 21, 231–238 (2001).
Yamamoto, T., Kuramoto, H. & Kadowaki, M. Downregulation in aquaporin 4 and aquaporin 8 expression of the colon associated with the induction of allergic diarrhea in a mouse model of food allergy. Life Sci. 81, 115–120 (2007).
Badaut, J. Aquaglyceroporin 9 in brain pathologies. Neuroscience 168, 1047–1057 (2010).
Ishibashi, K., Morinaga, T., Kuwahara, M., Sasaki, S. & Imai, M. Cloning and identification of a new member of water channel (AQP10) as an aquaglyceroporin. Biochim. Biophys. Acta 1576, 335–340 (2002).
Boone, M. & Deen, P. M. Congenital nephrogenic diabetes insipidus: what can we learn from mouse models? Exp. Physiol. 94, 186–190 (2009).
Acknowledgements
The authors' research is funded by the US National Institutes of Health (A.S.V. and M.O.A.), the Guthy-Jackson Charitable Foundation (A.S.V. and M.C.P.) and the Cystic Fibrosis Foundation (A.S.V.).
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A.S.V. is a named co-inventor on several aquaporin (AQP)-related patents, including a patent on aquaporin monoclonal antibodies to treat neuromyelitis optica (NMO). Patent rights are assigned to the University of California, San Francisco (UCSF).
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Glossary
- Aquaglyceroporin
-
A class of the aquaporins (AQP3, AQP7 and AQP9) that transport glycerol in addition to water.
- Virtual screening
-
A computational technique that is used to identify small-molecule modulators of a drug target. This is typically conducted in a structure-based manner (using protein–ligand docking) or in a ligand-based manner (using similarity searching or through the use of pharmacophore models).
- Molecular dynamics simulations
-
Computational methods that simulate the physical motion of atoms and molecules. When applied to biomolecules, the results are typically trajectories of the atoms of the protein, solvent, ions, bound ligands and so on, over timescales that range from nanoseconds to microseconds.
- Grotthuss-type 'proton-wire' mechanism
-
A hypothesis for proton movement in bulk water, where a proton can 'hop' along a continuous line of water molecules in a hydrogen-bonded network, with the resultant reorientation of water molecules after the transfer has occurred.
- Free-energy profiles
-
A term that is used to describe the estimated energetics of a molecule passing through the span of a channel protein; it is usually calculated by molecular dynamics simulations.
- Salt transport-blocking diuretics
-
Drugs that inhibit the absorption of Na+, K+ and Cl−ions in the kidney and therefore secondarily inhibit water absorption. For example, amiloride inhibits the epithelial sodium channel in the distal tubule, and furosemide inhibits the Na+/K+/2Cl− symporter in the thick ascending limb of the loop of Henle.
- Aquaretic response
-
The urinary elimination of water without electrolyte loss (as opposed to a diuretic response in which urinary elimination of water is secondary to the elimination of salt).
- Astrocyte end-feet
-
Astrocyte processes that surround microvascular endothelial cells in the central nervous system.
- Vasogenic oedema
-
Oedema in the central nervous system where water accumulates in extracellular spaces.
- Cortical spreading depression
-
A wave of depolarization that spreads in the brain and is followed by the suppression of brain activity.
- Glial scar
-
A scar in the central nervous system that is formed in response to damage and involves reactive astrocytes and microglia.
- Density functional theory calculations
-
A computational method that uses quantum-mechanical theory to model the energy and chemical structure of molecules.
- Infiltrating tumour cells
-
Tumour cells that spread into normal tissue such that there is no clear border between the tumour and the normal tissue.
- Stratum corneum
-
The outermost layer of the epidermis that is composed of dead cells (that is, keratinocytes).
- Lens fibres
-
Long, thin transparent cells that form the bulk of the lens, arranged in concentric layers.
- Gap junction channels
-
Intercellular channels composed of connexin proteins that allow the passage of small molecules (typically <1 kDa) between cells.
- Palmoplantar keratoderma
-
A disease that is characterized by abnormal thickening of the skin on the palms of hands and soles of feet.
- Ussing chamber
-
An apparatus in which a cell layer separates two solution compartments; it is used to measure ion transport.
- Stopped-flow measurements
-
Assays that are carried out using an apparatus in which two solutions are mixed together rapidly (in <1 millisecond) and have an optical read-out.
- IC50 value
-
The concentration of a compound that produces 50% inhibition of a target function.
- Parotiditis
-
Inflammation of the parotid salivary gland.
- Therapeutic apheresis
-
The passage of blood through a filtering apparatus to remove or inactivate a pathogenic substance.
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Verkman, A., Anderson, M. & Papadopoulos, M. Aquaporins: important but elusive drug targets. Nat Rev Drug Discov 13, 259–277 (2014). https://doi.org/10.1038/nrd4226
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DOI: https://doi.org/10.1038/nrd4226
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