The molecular basis of water transport in the brain

Key Points

  • 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.

Abstract

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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Figure 1: Diagram showing members of the aquaporin (Aqp) family expressed in mammals.
Figure 2: Architecture of the aquaporin-1 (Aqp1) water channel (longitudinal section through an individual subunit).
Figure 3: Aquaporins in the brain.
Figure 4: Aqp4 expression at the blood—brain interface
Figure 5: Effect of α-syntrophin (α-Syn) deletion on aquaporin-4 (Aqp4) distribution.
Figure 6: Homeostatic functions of astrocytes.
Figure 7: Expression pattern of aquaporin-4 (Aqp4) in the subfornical organ of rat.

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Acknowledgements

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.

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Correspondence to Ole P. Ottersen.

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DATABASES

LocusLink

aquaporins

Eaat1

Glut1

Mct1

Mdx

α-Syn

Glossary

PROTEOLIPOSOME

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.

TANYCYTE

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.

ELECTRORETINOGRAM

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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