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Current Understanding of the Cellular Biology and Molecular Structure of the Antidiuretic Hormone-stimulated Water Transport Pathway

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Title: Current Understanding of the Cellular Biology and Molecular Structure of the Antidiuretic Hormone-stimulated Water Transport Pathway
Authors: Harris, H. William; Strange, Kevin; Zeidel, Mark L.
Publisher: Journal of Clinical Investigation
Date Published: July 01, 1991
Reference Number: 276
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

The antidiuretic hormone, vasopressin (VP) helps the kidney conserve water and concentrate urine. It does this by initiating a molecular process beginning in the basolateral membranes of the principal cells of the kidney collecting duct (CD). This process inserts water channels (WCs) in the apical membrane of the collecting duct cells. The WCs are proteins which act as channels through which water can flow out of the cells into the kidneys' inner tissue.

This picture of VP-stimulated water transport has been pieced together over time by many researchers, and it is constantly being refined as improvements in testing methodology give researchers more accurate measures. In this article, Harris, et al. discuss the current understanding of the cellular biology and molecular structure of the VP water channel. They draw on research on toad urinary bladder granual epithelial cells and mammalian CD principal cells as both behave similarly in response to VP.

Think of the CD principal cells as having the shape of an upright rectangle. The part of the cell membrane running around the bottom and sides of the cell are referred to as the basolateral membrane. The part running around the top of the cell is the apical membrane.

The CD cell apical membrane has a low water permeability. That is, when the hormone VP is not present, water does not readily pass through the apical membrane. Scientists are unclear as to why it has such a low permeability. Perhaps the lipids (fats) of which they are constructed have an unusual construction, or perhaps the lipids are uniquely arranged. Or perhaps the way the lipids are distributed in the membrane bilayer is the determinant factor.

When VP is present in the CD principal cells, the degree of water permeability of the apical membrane immediately increases by four hundred. This increase is the result of specific WCs being inserted in the apical membranes. Evidence for this is grouped in three areas:

  1. The permeability changes elicited by VP are relatively selective for water. That is, the WC might only allow water to pass through it, not larger molecules.
  2. A large number of ultrastructural studies have identified structures called membrane particle aggregates appear in the apical membrane simultaneously with the VP-elicited increase in apical membrane water permeability.
  3. Biophysical studies of VP elicited water flow are best explained by WCs, as opposed to simple water diffusion through the lipid bilayer.

A large body of evidence now supports the membrane shuttling hypothesis. This states that the WCs specific to the apical membranes await within little sacs called vesicles inside the CD principal cells, just beneath the apical membrane. When VP is present in the cells, it sends a signal to these WC-bearing vesicles to travel from their holding sites to the apical membrane. There they fuse with it and the WCs insert themselves into the apical membrane, making it more water permeable.

When VP absents itself, the WC-bearing vesicles retrieve the WCs and bring them back to their holding site. From there, the vesicles recycle back to the apical membrane with at least some of the WCs when VP presents itself to the cell again. Many types of vesicles, upon returning from the membrane to inside the cell, acidify and dissolve their contents. But preliminary studies suggest that these WC-bearing vesicles do not do this, and may instead keep the WCs intact for repeated use.

Biophysical techniques have also provided insight into the likely features of this VP water channel:

  1. The WC appears to be a protein or a complex of proteins in which sulfhydryl groups play an important role.
  2. The WC-bearing vesicles have an extraordinarily high degree of water permeability, suggesting they contain VP water channels at an extraordinarily high density.
  3. Water molecules traverse through the VP water channel in single file fashion, indicating a very small opening for the water molecules to pass through.
  4. The VP water channel might also be permeable to the hydronium ion. Alternatively, proteins may cross the water channel by a sequential association-dissociation with water molecules within the channel.

Researchers are currently attempting to identify, purify and clone proteins of the VP water channel. They concluded the WC protein(s) would have to meet the following criteria. It must be:

  1. resent on the apical surface exclusively during VP stimulation.
  2. removed from the apical membrane during withdrawal of VP stimulation.
  3. resent in vesicles carrying VP water channels from the apical membrane into the cell.
  4. made of integral membrane proteins that bind membrane lipids.
  5. of a size to span the width of the WC-bearing vesicles.
  6. a large proportion of the protein found in WC-bearing vesicle.
  7. inhibited by mercurial compounds.


Researchers have isolated and identified a 55-kD (kilo Dalton) and 53-kD proteins that meets these requirements. This suggests that these proteins are components of the VP water channel.