Genetic defects involving aquaporin genes have been associated with several human diseases. The 2003 Nobel Prize in Chemistry was awarded to Peter Agre for the discovery of aquaporins and jointly to Roderick MacKinnon for his work on the structure and mechanism of potassium channels.
Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.
The pioneering discoveries and research on water channels by Agre and his colleagues resulted in the presentation of a Nobel Prize in Chemistry to Agre in 2003. In 1999, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure of an aquaporin, viz. aquaporin-1. Further studies using supercomputer simulations have identified the pathway of water as it moves through the channel and demonstrated how a pore can allow water to pass without the passage of small solutes.
However the first report of protein mediated water transport through membranes was by Gheorghe Benga in 1986. This publication which preceded Agre"s first publication on water membrane transport proteins has led to a controversy that Benga's work was neither adequately recognized by Agre nor the Nobel Prize Committee.
Aquaporin proteins are made up of six transmembrane α-helices arranged in a right-handed bundle, with the amino and the carboxyl termini located on the cytoplasmic surface of the membrane. The amino and carboxyl halves of the sequence show similarity to each other, in what appears to be a tandem repeat. Some researches believe that this results from an early evolution event which saw the duplication of the half-sized gene. There are also five interhelical loop regions (A – E) that form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops which contain the highly, although not completely conserved Asn-Pro-Ala (NPA) motif, which overlap the middle of the lipid bilayer of the membrane forming a 3-D 'hourglass' structure where the water flows through. This overlap forms one of the two well-known channel constriction sites in the peptide, the NPA motif and a second and usually narrower constriction known as 'selectivity filter' or ar/R selectivity filter.
Aquaporins form tetramers in the cell membrane, with each monomer acting as a water channel. The different aquaporins contain differences in their peptide sequence which allows for the size of the pore in the protein to differ between aquaporins. The resultant size of the pore directly affects what molecules are able to pass through the pore, with small pore sizes only allowing small molecules like water to pass through the pore.
Why this rotation occurs is not entirely clear yet. Some researchers identified an electrostatic field generated by the two aquaporin half helices HB and HE as the reason for the rotation of water molecules. Others suggested that it is caused by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. Moreover, whether the rotation of water molecules has any biological significance is still being discussed. Early studies speculated that the "bipolar" orientation of water molecules keep them from conducting protons via the Grotthuss mechanism, while still permitting a fast flux of water molecules. More recent studies question this interpretation and emphasize an electrostatic barrier as the reason for proton blockage. In the latter view, the rotation of water molecules is only a side effect of the electrostatic barrier. At present (2008), the origin of the electrostatic field is a matter of debate. While some studies mainly considered the electric field generated by the protein's half helices HB and HE, others emphasized desolvation effects as the proton enters the narrow aquaporin pore.
The ar/R (aromatic/arginine) selectivity filter is a cluster of amino acids that help bind to water molecules and exclude other molecules that may try to enter the pore. It is the mechanism by which the aquaporin is able to selectively bind water molecules (hence allowing them through) and prevent other molecules from entering. The ar/P filter is a tetrad that is formed by two amino acid residues from helices 2 (H2) and 5 (H5) and two residues from loop E (LE1 and LE2), found on either side of the NPA motif. The ar/R region is usually found towards the extracellular vestibule, approximately 8 Å above the NPA motif and is often the narrowest part of the pore. The narrow pore acts to weaken the hydrogen bonds between the water molecules allowing the water to interact with the positively charged arginine, which also acts as a proton filter for the pore.
|Aquaporin 1||Water reabsorption|
|Aquaporin 2||Water reabsorption in response to ADH|
|Aquaporin 3||Water reabsorption|
|Aquaporin 4||Water reabsorption|
Aquaporins in plants are separated into four main homologous subfamilies, or groups:
These four subfamilies have later been divided into smaller evolutionary subgroups based on their DNA sequence. PIPs cluster into two subgroups, PIP1 and PIP2, whilst TIPs cluster into 5 subgroups, TIP1, TIP2, TIP3, TIP4 and TIP5. Each subgroup is again split up into isoforms e.g. PIP1;1, PIP1;2.
The silencing of plant aquaporins has been linked to poor plant growth and even death of the plant.
There have been two clear examples of diseases identified as resulting from mutations in aquaporins:
A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they are generally healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by countercurrent multiplication.
In addition to its role in genetically determined nephrogenic diabetes insipidus, aquaporins also play a key role in acquired forms of nephrogenic diabetes insipidus (disorders that cause increased urine production). Acquired nephrogenic diabetes insipidus can result from impaired regulation of aquaporin-2 due to administration of lithium salts (as a treatment for bipolar disorder), low potassium concentrations in the blood (hypokalemia), high calcium concentrations in the blood (hypercalcemia), or a chronically high intake of water beyond the normal requirements (e.g. due to excessive habitual intake of bottled water or coffee).