The first aquaporin was identified in 1992. This family of specialized water channels now contains 11 mammalian members that are localized to various organs including kidney, secretory glands and brain.
Aquaporins assemble in membranes as homotetramers, wherein each monomer comprises a water channel and six membrane-spanning α-helical domains. Extensive homology between the intracellular carboxyl (C) and amino (N) termini is characteristic of aquaporins.
Aquaporins facilitate the passive bidirectional movement of water that is driven by osmotic gradients across membranes.
Three aquaporins — Aqp1, Aqp4 and Aqp9 — have been localized in the brain.
Aqp1 is expressed in the apical membrane of the epithelium of the choroid plexus where it probably contributes to the production of cerebrospinal fluid.
Aqp9 is expressed in the ependymal lining of the third ventricle, and probably also in astrocytes and epithelial cells. Aqp9 belongs to a subfamily of aquaporins — the aquaglyceroporins — that transport glycerol as well as water, and might therefore participate in energy metabolism.
Aqp4 is the predominant and best-characterized aquaporin in brain, and is principally located in the plasma membrane of astrocytes. Evidence indicates that Aqp4 is anchored in these membranes through interactions with α-syntrophin.
Aqp4 probably mediates the exchange of water between brain and extracerebral liquids, therefore playing an important part in the maintenance of ion and volume homeostasis. Specific functions might include efflux of metabolically generated excess water and permissive facilitation of extracellular K+ clearance.
Aquaporins have been linked to several pathophysiological conditions including brain oedema, and epileptic seizures, and might be new targets for therapeutic intervention.
Brain function is inextricably coupled to water homeostasis. The fact that most of the volume between neurons is occupied by glial cells, leaving only a narrow extracellular space, represents an important challenge, as even small extracellular volume changes will affect ion concentrations and therefore neuronal excitability. Further, the ionic transmembrane shifts that are required to maintain ion homeostasis during neuronal activity must be accompanied by water. It follows that the mechanisms for water transport across plasma membranes must have a central part in brain physiology. These mechanisms are also likely to be of pathophysiological importance in brain oedema, which represents a net accumulation of water in brain tissue. Recent studies have shed light on the molecular basis for brain water transport and have identified a class of specialized water channels in the brain that might be crucial to the physiological and pathophysiological handling of water.
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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). Identification of the first member of the aquaporin family (Chip28, later renamed Aqp1).
Agre, P. et al. Aquaporin water channels — from atomic structure to clinical medicine. J. Physiol. (Lond.) 542, 3–16 (2002).
Johansson, I., Karlsson, M., Johanson, U., Larsson, C. & Kjellbom, P. The role of aquaporins in cellular and whole plant water balance. Biochim. Biophys. Acta 1465, 324–342 (2000).
Santoni, V., Gerbeau, P., Javot, H. & Maurel, C. The high diversity of aquaporins reveals novel facets of plant membrane functions. Curr. Opin. Plant Biol. 3, 476–481 (2000).
Marples, D., Knepper, M. A., Christensen, E. I. & Nielsen, S. Redistribution of aquaporin-2 water channels induced by vasopressin in rat kidney inner medullary collecting duct. Am. J. Physiol. 269, C655–C664 (1995).
Agre, P. et al. Aquaporin CHIP: the archetypal molecular water channel. Am. J. Physiol. 265, F463–F476 (1993).
Nielsen, S., Smith, B. L., Christensen, E. I., Knepper, M. A. & Agre, P. CHIP28 water channels are localized in constitutively water-permeable segments of the nephron. J. Cell Biol. 120, 371–383 (1993).
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).
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). A member of the aquaporin family was cloned that was later named Aqp4.
Jung, J. S. et al. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc. Natl Acad. Sci. USA 91, 13052–13056 (1994).
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). High resolution immunogold analysis revealed a concentration of Aqp4 in subpial and perivascular endfeet, and in ependymal cells, that is, at the interfaces between brain and extracerebral liquids (blood and CSF).
Solenov, E., Watanabe, H., Manley, G. T. & Verkman A. S. Seven-fold reduced osmotic water permeability in primary astrocyte cultures from aquaporin-4 deficient mice measured by a calcein quenching method. Am. J. Physiol. Cell Physiol. (2003).
Bai, L., Fushimi, K., Sasaki, S. & Marumo, F. Structure of aquaporin-2 vasopressin water channel. J. Biol. Chem. 271, 5171–5176 (1996).
Shi, L. B., Skach, W. R. & Verkman, A. S. Functional independence of monomeric CHIP28 water channels revealed by expression of wild-type mutant heterodimers. J. Biol. Chem. 269, 10417–10422 (1994).
Skach, W. R. et al. Biogenesis and transmembrane topology of the CHIP28 water channel at the endoplasmic reticulum. J. Cell Biol. 125, 803–815 (1994).
Preston, G. M., Jung, J. S., Guggino, W. B. & Agre, P. Membrane topology of aquaporin CHIP. Analysis of functional epitope-scanning mutants by vectorial proteolysis. J. Biol. Chem. 269, 1668–1673 (1994).
Chandy, G., Zampighi, G. A., Kreman, M. & Hall, J. E. Comparison of the water transporting properties of MIP and Aqp1. J. Membr. Biol. 159, 29–39 (1997).
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).
Farinas, J., Van Hoek, A. N., Shi, L. B., Erickson, C. & Verkman, A. S. Nonpolar environment of tryptophans in erythrocyte water channel CHIP28 determined by fluorescence quenching. Biochemistry 32, 11857–11864 (1993).
Van Hoek, A. N. & Verkman, A. S. Functional reconstitution of the isolated erythrocyte water channel CHIP28. J. Biol. Chem. 267, 18267–18269 (1992).
Zeidel, M. L., Ambudkar, S. V., Smith, B. L. & Agre, P. Reconstitution of functional water channels in liposomes containing purified red cell CHIP28 protein. Biochemistry 31, 7436–7440 (1992).
Yang, B. & Verkman, A. S. Water and glycerol permeabilities of aquaporins 1–5 and MIP determined quantitatively by expression of epitope-tagged constructs in Xenopus oocytes. J. Biol. Chem. 272, 16140–16146 (1997).
Tsukaguchi, H. et al. Molecular characterization of a broad selectivity neutral solute channel. J. Biol. Chem. 273, 24737–24743 (1998).
de Groot, B. L. & Grubmuller, H. Water permeation across biological membranes: mechanism and dynamics of aquaporin-1 and GlpF. Science 294, 2353–2357 (2001).
Murata, K. et al. Structural determinants of water permeation through aquaporin-1. Nature 407, 599–605 (2000).
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). This study describes an atomic model for Aqp1, revealing the three-dimensional structure of aqueous pore and providing an explanation of the water selectivity.
Fu, D. et al. Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290, 481–486 (2000).
Thomas, D. et al. Aquaglyceroporins, one channel for two molecules. Biochim. Biophys. Acta 1555, 181–186 (2002).
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).
Yasui, M. et al. Rapid gating and anion permeability of an intracellular aquaporin. Nature 402, 184–187 (1999).
Hazama, A., Kozono, D., Guggino, W. B., Agre, P. & Yasui, M. Ion permeation of Aqp6 water channel protein. Single channel recordings after Hg2+ activation. J. Biol. Chem. 277, 29224–29230 (2002).
Katsura, T., Gustafson, C. E., Ausiello, D. A. & Brown, D. Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. Am. J. Physiol. 272, F817–F822 (1997).
Fushimi, K., Sasaki, S. & Marumo, F. Phosphorylation of serine 256 is required for cAMP-dependent regulatory exocytosis of the aquaporin-2 water channel. J. Biol. Chem. 272, 14800–14804 (1997).
Brown, D. The ins and outs of aquaporin-2 trafficking. Am. J. Physiol. Renal Physiol. 284, F893–F901 (2003).
Xu, D. L. et al. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J. Clin. Invest 99, 1500–1505 (1997).
Han, Z., Wax, M. B. & Patil, R. V. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J. Biol. Chem. 273, 6001–6004 (1998).
Niermann, H., Amiry-Moghaddam, M., Holthoff, K., Witte, O. W. & Ottersen, O. P. A novel role of vasopressin in the brain: modulation of activity-dependent water flux in the neocortex. J. Neurosci. 21, 3045–3051 (2001).
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).
Carmosino, M. et al. Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human Aqp4-expressing gastric cells. J. Cell Biol. 154, 1235–1243 (2001).
Ke, C., Poon, W. S., Ng, H. K., Pang, J. C. & Chan, Y. Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci. Lett. 301, 21–24 (2001).
Kiening, K. L. et al. Decreased hemispheric aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci. Lett. 324, 105–108 (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).
Sato, S. et al. Expression of water channel mRNA following cerebral ischemia. Acta Neurochir. Suppl 76, 239–241 (2000).
Taniguchi, M. et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res. Mol. Brain Res. 78, 131–137 (2000).
Vizuete. M. L. et al. Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol. Dis. 6, 245–258 (1999).
Nakahama, K., Nagano, M., Fujioka, A., Shinoda, K. & Sasaki, H. Effect of TPA on aquaporin 4 mRNA expression in cultured rat astrocytes. Glia 25, 240–246 (1999).
Yamamoto, N. et al. Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res. Mol. Brain Res. 95, 110–116 (2001).
Arima, H. et al. Hyperosmolar mannitol stimulates expression of aquaporin 4 and 9 through a p38 mitogen activated protein kinase-dependent pathway in rat astrocytes. J. Biol. Chem. (2003).
Wu, Q., Delpire, E., Hebert, S. C. & Strange, K. Functional demonstration of Na+-K+-2Cl− cotransporter activity in isolated, polarized choroid plexus cells. Am. J. Physiol. 275, C1565–C1572 (1998).
Speake, T., Freeman, L. J. & Brown, P. D. Expression of aquaporin 1 and aquaporin 4 water channels in rat choroid plexus. Biochim. Biophys. Acta 1609, 80–86 (2003).
Nejsum, L. N. et al. Functional requirement of aquaporin-5 in plasma membranes of sweat glands. Proc. Natl Acad. Sci. USA 99, 511–516 (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).
Davson, H. & Bradbury, M. The fluid exchange of the central nervous system. Symp. Soc. Exp. Biol. 19, 349–364 (1965).
Zeuthen, T. & Wright, E. M. An electrogenic Na+/K+ pump in the choroid plexus. Biochim. Biophys. Acta 511, 517–522 (1978).
Wright, E. M. Transport processes in the formation of the cerebrospinal fluid. Rev. Physiol Biochem. Pharmacol. 83, 3–34 (1978).
Keep, R. F., Xiang, J. & Betz, A. L. Potassium cotransport at the rat choroid plexus. Am. J. Physiol. 267, C1616–C1622 (1994).
Plotkin, M. D. et al. Expression of the Na+-K+-2Cl− cotransporter BSC2 in the nervous system. Am. J. Physiol. 272, C173–C183 (1997).
Nakamura, N. et al. Inwardly rectifying K+ channel Kir7.1 is highly expressed in thyroid follicular cells, intestinal epithelial cells and choroid plexus epithelial cells: implication for a functional coupling with Na+,K+-ATPase. Biochem. J. 342, 329–336 (1999).
Lindsey, A. E. et al. Functional expression and subcellular localization of an anion exchanger cloned from choroid plexus. Proc. Natl Acad. Sci. USA 87, 5278–5282 (1990).
Alper, S. L., Stuart-Tilley, A., Simmons, C. F., Brown, D. & Drenckhahn, D. The fodrin-ankyrin cytoskeleton of choroid plexus preferentially colocalizes with apical Na+K+-ATPase rather than with basolateral anion exchanger AE2. J. Clin. Invest. 93, 1430–1438 (1994).
Frigeri, A. et al. Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. J. Cell Sci. 108, 2993–3002 (1995).
Frigeri, A., Nicchia, G. P., Verbavatz, J. M., Valenti, G. & Svelto, M. Expression of aquaporin-4 in fast-twitch fibers of mammalian skeletal muscle. J. Clin. Invest. 102, 695–703 (1998).
Takumi, Y. et al. Select types of supporting cell in the inner ear express aquaporin-4 water channel protein. Eur. J. Neurosci. 10, 3584–3595 (1998).
Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and Aqp4 in specific membrane domains. Glia 26, 47–54 (1999). This study showed that Kir4.1, a K+ channel known to be involved in K+ clearance, is strictly co-localized with Aqp4, indicating that the two membrane molecules act in concert.
Kobayashi, H. et al. Aquaporin subtypes in rat cerebral microvessels. Neurosci. Lett. 297, 163–166 (2001).
Amiry-Moghaddam, M. Molecular basis of water homeostasis in brain. Thesis, Univ. Oslo. (2003).
Adams, M. E., Mueller, H. A. & Froehner, S. C. In vivo requirement of the α-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4. J. Cell Biol. 155, 113–122 (2001).
Peters, M. F., Adams, M. E. & Froehner, S. C. Differential association of syntrophin pairs with the dystrophin complex. J. Cell Biol. 138, 81–93 (1997).
Adams, M. E. et al. Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J. Cell Biol. 150, 1385–1398 (2000).
Albrecht, D. E. & Froehner, S. C. Syntrophins and dystrobrevins: defining the dystrophin scaffold at synapses. Neurosignals 11, 123–129 (2002).
Froehner, S. C., Adams, M. E., Peters, M. F. & Gee, S. H. Syntrophins: modular adapter proteins at the neuromuscular junction and the sarcolemma. Soc. Gen. Physiol Ser. 52, 197–207 (1997).
Wertz, K. & Fuchtbauer, E. M. Dmdmdx-βgeo: A new allele for the mouse dystrophin gene. Dev. Dyn. 212, 229–241 (1998).
Frigeri, A. et al. Aquaporin-4 deficiency in skeletal muscle and brain of dystrophic mdx mice. FASEB J. 15, 90–98 (2001).
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). This study showed that selective removal of perivascular Aqp4 by α-Syn deletion reduced the extent of post-ischaemic oedema and that the binding between Aqp4 and α-Syn is sensitive to ischaemia.
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).
Wen, H. et al. Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Eur. J. Neurosci. 11, 935–945 (1999).
Nico, B. et al. Role of aquaporin-4 water channel in the development and integrity of the blood-brain barrier. J. Cell Sci. 114, 1297–1307 (2001).
Newman, E. A., Frambach, D. A. & Odette, L. L. Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science 225, 1174–1175 (1984).
Newman, E. A. Regional specialization of the membrane of retinal glial cells and its importance to K+ spatial buffering. Ann. NY Acad. Sci. 481, 273–286 (1986).
Gardner-Medwin, A. R., Coles, J. A. & Tsacopoulos, M. Clearance of extracellular potassium: evidence for spatial buffering by glial cells in the retina of the drone. Brain Res. 209, 452–457 (1981).
Dietzel, I., Heinemann, U., Hofmeier, G. & Lux, H. D. Transient changes in the size of the extracellular space in the sensorimotor cortex of cats in relation to stimulus-induced changes in potassium concentration. Exp. Brain Res. 40, 432–439 (1980).
Lux, H. D., Heinemann, U. & Dietzel, I. Ionic changes and alterations in the size of the extracellular space during epileptic activity. Adv. Neurol. 44, 619–639 (1986).
Holthoff, K. & Witte, O. W. Directed spatial potassium redistribution in rat neocortex. Glia 29, 288–292 (2000).
Sarfaraz, D. & Fraser, C. L. Effects of arginine vasopressin on cell volume regulation in brain astrocyte in culture. Am. J. Physiol. 276, E596–E601 (1999).
Sykova, E., Vargova, L., Prokopova, S. & Simonova, Z. Glial swelling and astrogliosis produce diffusion barriers in the rat spinal cord. Glia 25, 56–70 (1999).
Sykova, E. & Chvatal, A. Extracellular ionic and volume changes: the role in glia-neuron interaction. J. Chem. Neuroanat. 6, 247–260 (1993).
Sykova, E. Modulation of spinal cord transmission by changes in extracellular K+ activity and extracellular volume. Can. J. Physiol. Pharmacol. 65, 1058–1066 (1987).
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).
Lehninger, A. L. Biochemistry, The Molecular Base of Cell Structure and Function (Worth, New York, 1970).
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 is the first study suggesting that Aqp4 has a role in the development of brain oedema.
Deleuze, C., Duvoid, A. & Hussy, N. Properties and glial origin of osmotic-dependent release of taurine from the rat supraoptic nucleus. J. Physiol. (Lond.) 507, 463–471 (1998).
Hussy, N., Deleuze, C., Pantaloni, A., Desarmenien, M. G. & Moos, F. Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: possible role in osmoregulation. J. Physiol. (Lond.) 502, 609–621 (1997).
Hussy, N., Deleuze, C., Desarmenien, M. G. & Moos, F. C. Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure. Prog. Neurobiol. 62, 113–134 (2000).
Elkjaer, M. et al. Immunolocalization of Aqp9 in liver, epididymis, testis, spleen, and brain. Biochem. Biophys. Res. Commun. 276, 1118–1128 (2000).
Carbrey, J. M. et al. Aquaglyceroporin Aqp9: solute permeation and metabolic control of expression in liver. Proc. Natl Acad. Sci. USA 100, 2945–2950 (2003).
Ishibashi, K. et al. Cloning and functional expression of a new aquaporin (Aqp9) abundantly expressed in the peripheral leukocytes permeable to water and urea, but not to glycerol. Biochem. Biophys. Res. Commun. 244, 268–274 (1998).
Venero, J. L., Vizuete, M. L., Machado, A. & Cano, J. Aquaporins in the central nervous system. Prog. Neurobiol. 63, 321–336 (2001).
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). Mdx mice that lacked Aqp4 at the interfaces between brain and blood/CSF showed a delayed development of hyponatremic oedema, compared with wild-type mice.
Cadnapaphornchai, M. A. & Schrier, R. W. Pathogenesis and management of hyponatremia. Am. J. Med. 109, 688–692 (2000).
Hise, M. A. & Johanson, C. E. The sink action of cerebrospinal fluid in uremia. Eur. Neurol. 18, 328–337 (1979).
Klatzo, I., Chui, E., Fujiwara, K. & Spatz, M. Resolution of vasogenic brain edema. Adv. Neurol. 28, 359–373 (1980).
Wolburg, H. Orthogonal arrays of intramembranous particles: a review with special reference to astrocytes. J. Hirnforsch. 36, 239–258 (1995).
Loo, D. D. F., Wright, E. M. & Zeuthen, T. Water pumps. J. Physiol. (Lond.) 542, 53–60 (2002).
Yan, Y., Dempsey, R. J. & Sun, D. Expression of Na+-K+-Cl− cotransporter in rat brain during development and its localization in mature astrocytes. Brain Res. 911, 43–55 (2001).
Nitta, T. et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell Biol. 161, 653–660 (2003).
Hamann, S., Kiilgaard, J. F., la Cour, M., Prause, J. U. & Zeuthen, T. Cotransport of H+, lactate, and H2O in porcine retinal pigment epithelial cells. Exp. Eye Res. 76, 493–504 (2003).
Zeuthen, T. & MacAulay, N. Cotransporters as molecular water pumps. Int. Rev. Cytol. 215, 259–284 (2002).
MacAulay, N., Gether, U., Klaerke, D. A. & Zeuthen, T. Water transport by the human Na+-coupled glutamate cotransporter expressed in Xenopus oocytes. J. Physiol. (Lond.) 530, 367–378 (2001).
Zeuthen, T. Molecular water pumps. Rev. Physiol Biochem. Pharmacol. 141, 97–151 (2000).
Zeuthen, T. et al. Water transport by the Na+/glucose cotransporter under isotonic conditions. Biol. Cell 89, 307–312 (1997).
MacAulay, N., Gether, U., Klaeke, D. A. & Zeuthen, T. Passive water and urea permeability of a human Na+-glutamate cotransporter expressed in Xenopus oocytes. J. Physiol. (Lond.) 542, 817–828 (2002).
Gerhart, D. Z., Enerson, B. E., Zhdankina, O. Y., Leino, R. L. & Drewes, L. R. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am. J. Physiol. (Lond.) 273, E207–E213 (1997).
Yu, S. & Ding, W. G. The 45 kDa form of glucose transporter 1 (GLUT1) is localized in oligodendrocyte and astrocyte but not in microglia in the rat brain. Brain Res. 797, 65–72 (1998).
Kacem, K., Lacombe, P., Seylaz, J. & Bonvento, G. Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study. Glia 23, 1–10 (1998).
McCall, A. L. et al. Forebrain ischemia increases GLUT1 protein in brain microvessels and parenchyma. J. Cereb. Blood Flow Metab. 16, 69–76 (1996).
Takakura, Y. et al. Hexose uptake in primary cultures of bovine brain microvessel endothelial cells. II. Effects of conditioned media from astroglial and glioma cells. Biochim. Biophys. Acta 1070, 11–19 (1991).
Bergersen, L., Rafiki, A. & Ottersen, O. P. Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system. Neurochem. Res. 27, 89–96 (2002).
Danbolt, N. C. et al. Properties and localization of glutamate transporters. Prog. Brain Res. 116, 23–43 (1998).
Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994).
Weed, L. H. & McKibben, P. S. Experimental alteration of brain bulk. Am. J. Physiol. 48, 531–558 (1919).
Li, J. & Verkman, A. S. Impaired hearing in mice lacking aquaporin-4 water channels. J. Biol. Chem. 276, 31233–31237 (2001).
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).
Worton, R. Muscular dystrophies: diseases of the dystrophin-glycoprotein complex. Science 270, 755–756 (1995).
Blake, D. J., Hawkes, R., Benson, M. A. & Beesley, P. W. Different dystrophin-like complexes are expressed in neurons and glia. J. Cell Biol. 147, 645–658 (1999).
Austin, R. C., Morris, G. E., Howard, P. L., Klamut, H. J. & Ray, P. N. Expression and synthesis of alternatively spliced variants of Dp71 in adult human brain. Neuromuscul. Disord. 10, 187–193 (2000).
Chelly, J. et al. Dystrophin gene transcribed from different promoters in neuronal and glial cells. Nature 344, 64–65 (1990).
Newey, S. E., Benson, M. A., Ponting, C. P., Davies, K. E. & Blake, D. J. Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex. Curr. Biol. 10, 1295–1298 (2000).
Kachinsky, A. M., Froehner, S. C. & Milgram, S. L. A PDZ-containing scaffold related to the dystrophin complex at the basolateral membrane of epithelial cells. J. Cell Biol. 145, 391–402 (1999).
Kozono, D., Yasui, M., King, L. S. & Agre, P. Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine. J. Clin. Invest. 109, 1395–1399 (2002).
We thank C. Knudsen and G. Lothe for help with the illustrations and P. Agre, H. Kimelberg and S. Froehner for invaluable advice. Supported by the Norwegian Research Council, the European Co-operation in Scientific and Technological Research (COST) and the European Union.
The authors declare no competing financial interests.
A liposome into which a specific protein, or group of proteins, has been incorporated.
- RETINAL MÜLLER CELL
The main glial elements of the retina that assume many of the functions that are carried out by astrocytes, oligodendrocytes and ependymal cells in other central nervous system regions.
- PDZ DOMAIN
A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, discs large, zona occludens 1).
- PLECKSTRIN HOMOLOGY DOMAIN
A sequence of about 100 amino acids that is present in many signalling molecules. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.
A type of ependymal cell found principally in the walls of the third ventricle of the brain. The tanycytes might have branched or unbranched processes, some of which end on capillaries or neurons.
Measurement of the retinal response to light, typically using an electrode attached to the cornea.
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Amiry-Moghaddam, M., Ottersen, O. The molecular basis of water transport in the brain. Nat Rev Neurosci 4, 991–1001 (2003). https://doi.org/10.1038/nrn1252
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