Aquaporins Increase the Water Permeability of Cell Membranes

As just noted, small changes in extracellular osmotic strength cause most animal cells to swell or shrink rapidly. In contrast, frog oocytes and eggs do not swell when placed in pond water of very low osmotic strength even though their internal salt (mainly KCl) concentration is comparable to that of other cells («150 mM KCl). These observations first led investigators to suspect that the plasma membranes of erythrocytes and other cell types, but not frog oocytes, contain water-channel proteins that accelerate the osmotic flow of water. The experimental results shown in Figure 7-25 demonstrate that the erythrocyte cell-surface protein known as aquaporin functions as a water channel.

▲ FIGURE 7-26 Structure of the water-channel protein aquaporin. (a) Structural model of the tetrameric protein comprising four identical subunits. Each subunit forms a water channel, as seen in this end-on view from the exoplasmic surface. One of the monomers is shown with a molecular surface in which the pore entrance can be seen. (b) Schematic diagram of the topology of a single aquaporin subunit in relation to the membrane. Three pairs of homologous transmembrane a helices (A and A', B and B', and C and C) are oriented in the opposite direction with respect to the membrane and are connected by two hydrophilic loops containing short non-membrane-spanning helices and conserved asparagine (N) residues. The loops bend into the cavity formed by the six transmembrane helices, meeting in the middle to form part of

In its functional form, aquaporin is a tetramer of identical 28-kDa subunits (Figure 7-26a). Each subunit contains six membrane-spanning a helices that form a central pore through which water moves (Figure 7-26b, c). At its center the «2-nm-long water-selective gate, or pore, is only 0.28 nm in diameter, which is only slightly larger than the diameter of a water molecule. The molecular sieving properties of the constriction are determined by several conserved hydrophilic amino acid residues whose side-chain and carbonyl groups extend into the middle of the channel. Several water molecules move simultaneously through the channel, each of which sequentially forms specific hydrogen bonds and displaces another water molecule downstream. The formation of hydrogen bonds between the oxygen atom of water and the amino groups of the side chains ensures that only water passes through the channel; even protons cannot pass through.

the water-selective gate. (c) Side view of the pore in a single aquaporin subunit in which several water molecules (red oxygens and white hydrogens) are seen within the 2-nm-long water-selective gate that separates the water filled cytosolic and extracellular vestibules. The gate contains highly conserved arginine and histidine residues, as well as the two asparagine residues (blue) whose side chains form hydrogen bonds with transported waters. (Key gate residues are highlighted in blue.) Transported waters also form hydrogen bonds to the main-chain carbonyl group of a cysteine residue. The arrangement of these hydrogen bonds and the narrow pore diameter of 0.28 nm prevent passage of protons (i.e., H3O+) or other ions. [After H. Sui et al., 2001, Nature 414:872. See also T Zeuthen, 2001, Trends Biochem. Sci. 26:77, and K. Murata et al., 2000, Nature 407:599.]

As is the case for glucose transporters, mammals express a family of aquaporins. Aquaporin 1 is expressed in abundance in erythrocytes; the homologous aquaporin 2 is found in the kidney epithelial cells that resorb water from the urine. Inactivating mutations in both alleles of the aquaporin 2 gene cause diabetes insipidus, a disease marked by excretion of large volumes of dilute urine. This finding establishes the etiology of the disease and demonstrates that the level of aquaporin 2 is rate-limiting for water transport by the kidney. Other members of the aqua-porin family transport hydroxyl-containing molecules such as glycerol rather than water. I

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