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Aquaporins: Water Channels


Water crosses cell membranes by two routes: by diffusion through the lipid bilayer and through water channels called aquaporins. Functional characterization of the first aquaporin was reported in 1992, but water channels were suspected to exist well before that time, because the osmotic permeability of some types of epithelial cells was much too large to be accounted for by simple diffusion through the plasma membrane.

A single human aquaporin-1 channel facilitates water transport at a rate of roughly 3 billion water molecules per second. Such transport appears to be bidirectional, in accordance with the prevailing osmotic gradient.

The classical aquaporins transport solute-free water across cell membranes; they appear to be exclusive water channels and do not permeate membranes to ions or other small molecules. Some aquaporins - known as aquaglyceroporins - transport water plus glycerol and a few other small molecules.

The Aquaporin Family

More than 10 different mammalian aquaporins have been identified to date, and additional members are suspected to exist. Closely related water channel proteins have been isolated from plants, insects and bacteria. Aquaporin-1 from human red blood cells was the first to be discovered and is probably the best studied.

Hydrophobicity plots of their amino acid sequences predict that the aquaporins have six membrane-spanning segments, as depicted in the model of aquaporin-1 to the right.

Based on studies with aquaporin-1, it appears that aquaporins exist in the plasma membrane as homotetramers. Each aquaporin monomer contains two hemi-pores, which fold together to form a water channel.

Different aquaporins have different patterns of glycosylation. In the case of aquaporin-1, the peptide backbone is roughly 28 kDa and the glycosylated forms range from 40 to 60 kDa in mass. Most aquaporins have a protein kinase A phosphorylation motif in one of the cytoplasmic loops, and differential phosphorylation is suspected empart a regulatory function to the molecule.

Patterns of Aquaporin Expression

Each of the aquaporins has an essentially unique pattern of expression among tissues and during development. A summary of these attributes and some of the important potential or known functions is presented in the following table:


Major Sites of Expression Comments
Aquaporin-0 Eye: lens fiber cells Fluid balance within the lens
Aquaporin-1 Red blood cells Osmotic protection
Kidney: proximal tubule Concentration of urine
Eye: ciliary epithelium Production of aqueous humor
Brain: choriod plexus Production of cerebrospinal fluid
Lung: alveolar epithelial cells Alveolar hydration state
Aquaporin-2 Kidney: collecting ducts Mediates antidiuretic hormone activity
Aquaporin-3 * Kidney: collecting ducts Reabsorbtion of water into blood
Trachea: epithelial cells Secretion of water into trachea
Aquaporin-4 Kidney: collecting ducts Reabsorbtion of water
Brain: ependymal cells CSF fluid balance
Brain: hypothalamus Osmosensing function?
Lung: bronchial epithelium Bronchial fluid secretion
Aquaporin-5 Salivary glands Production of saliva
Lacrimal glands Production of tears
Aquaporin-6 Kidney Very low water permeability; function?
Aquaporin-7 * Fat cells Transports glycerol out of adipocytes
Testis and sperm
Aquaporin-8 Testis, pancreas, liver, others
Aquaporin-9 * Leukocytes
* an aquaglyceroporin

It should be clear that aquaporins are very widely distributed, and also that the different aquaporins have different functionally-important specialties.

Several interesting and important features of aquaporin-mediated water transport are illustrated in the principal cells that line collecting ducts in the kidney. Water flowing through these ducts can either continue on and be voided in urine or be reabsorbed across the epithelium and back into blood. Reabsorption is essentially nil unless the epithelial cells see antidiuretic hormone, which strongly stimulates reabsorption of water. Collecting duct cells express at least two aquaporins:

  • Aquaporin-2 is synthesized but, in the absense of antidiuretic hormone, resides in a pool of membrane vesicles within the cytoplasm. Binding of antidiuretic hormone to its receptor in the cell not only stimulates transcription of the aquaporin-2 gene, but causes the intracellular pool of aquaporin-2 to be inserted into the apical membrane. The cell is now able to efficiently take up water from the lumen of the duct.
  • Aquaporin-3 is constitutively expressed in the basolateral membrane of the cell. When water floods into the cell through aquaporin-2 channels, it can rapidly exit the cell through the aquaporin-3 channels and flow into blood.

Aquaporins and Disease

Considering the importance of water transport in a myriad of physiologic processes, it is to be expected that lesions in aquaporin genes or acquired dysfunction in aquaporins may cause or contribute to several disease states. The search for such connections is still early, but two clear examples of disease have been identified as resulting from deficiency in aquaporins:

  • Mutations in the aquaporin-2 gene cause hereditary nephrogenic diabetes insipidus in humans.
  • Mice homozygous for inactivating mutations in the aquaporin-0 gene develop congenital cataracts.
  • Adult-onset obesity develops in mice homozygous for inactivating mutations int he aquaporin-7 gene, presumably due to inefficiency in transporting glycerol from hydrolyzed triglyceride stores.

A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they appear clinically unaffected, but have not been examined under conditions of water deprivation. Mice with targeted deletions in aquaporin-1 also appear normal and healthy unless they are fluid restricted, in which case they become severely hyperosmolar.

References and Reviews

  • Borgnia M, Nielsen S, Engel A, Agre P: Cellular and molecular biology of aquaporin water channels. Annu Rev Biochem 68:425, 1999.
  • deGroot BL, Grubmuller H: Water permeation across biological membranes: Mechanism and dynamics of aquaporin-1 and GlpF. Science 294:2353, 2001.
  • Hibuse T, Proc Nat Acad Sci (USA) 102:10993, 2005.
  • King LS, Agre P: Pathophysiology of the aquaporin water channels. Annu Rev Physiol 58:619, 1998.
  • Knepper MA, Inoue T: Regulation of aquaporin-2 water channel trafficking by vasopressin. Curr Opinion Cell Biol 9:560, 1997.
  • Lee MD, King LS, Agre P: The aquaporin family of water channel proteins in clinical medicine. Medicine 76:141, 1997.
  • Preston GM, Carroll TP, Guggino WP Agre P: Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256:385, 1992.
  • Sasaki S, Ishibashi K, Marumo F: Aquaporin-2 and -3: Representatives of two subgroups of the aquaporin family colocalized in the kidney collecting duct. Annu Rev Physiol 60:199, 1998.

Last updated on Nov 28, 2005
Author: R. Bowen
Send comments via form or email to rbowen@colostate.edu