Aquaporin
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Aquaporins are a class of integral membrane proteins or more commonly refered as a class of major intrinsic proteins (MIP) that form pores in the membrane of biological cells. Aquaporins selectively conduct water molecules in and out, while preventing the passage of ions and other solutes. Also known as water channels, aquaporins are membrane pore proteins. Aquaporins are commonly composed of four (typically) identical subunit proteins in mammals, with each monomer acting as a water channel. Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water. Many human cell types express them, as do certain bacteria and many other organisms, such as plants for which it is essential for the water transport system. 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 aquapoirns and jointly to Roderick MacKinnon for his work on the structure and operation of ion channels.
There are thirteen known types of aquaporins in mammals, and six of these are located in the kidney. The most studied aquaporins are AQP1, AQP2, AQP3, and AQP4.
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[edit] Structure
Aquaporins 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, and facilitate the transport of water and, in some cases, other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane depending on the size of the pore. 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 moluceles like water to pass through the pore. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of membrane's electrochemical potential.
[edit] NPA motif
Using computer simulations it has been suggested that the orientation of the water molecules moving through the channel assures that only water passes between cells, due to the formation of a single line of water molecules. The water molecules move through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Upon entering, the water molecules face with their oxygen atom down the channel. Midstream, they reverse orientation, facing with the oxygen atom up. This rotation of the water molecules in the pore is carried out by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. While passing through the channel, the single-file chain of water molecules streams through, always entering face down and leaving face up. The strictly opposite orientations of the water molecules keep them from conducting protons (or rather oxonium ions, H3O+), while still permitting a fast flux of water molecules .
[edit] ar/R selectivity filter
The ar/R (aromatic/arginine) selectivity filter is a tetrad that is formed by two residues from helices 2 (H2) and 5 (H5) and two residues form 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 8Å 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.
[edit] History
In most cells, water moves in and out by diffusion through the lipid component of cell membranes. Due to the relatively high water permeability of some epithelial cells it was long suspected that some additional mechanism for water transport across membranes must exist, but it was not until 1992 that the functional characterization of the first aquaporin, ‘aquaporin-1’ (originally known as CHIP), was reported by Peter Agre, then of Johns Hopkins University and now a professor and administrator at Duke University. 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 2000, 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.
[edit] Aquaporin 1
AQP1 is a widely expressed water channel, whose physiological function has been most thoroughly characterized in the kidney. It is found in the basolateral and apical plasma membranes of the proximal tubules, the descending limb of the loop of Henle, and in the descending portion of the vasa recta. Additionally, it is found in red blood cells, vascular endothelium, the gastrointestinal tract, sweat glands, and lungs. It is not regulated by vasopressin (ADH).
[edit] Aquaporin 2
AQP2 is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. This aquaporin is regulated in two ways by the peptide hormone vasopressin: short-term regulation (minutes) through trafficking of AQP2 vesicles to the apical region where they fuse with the apical plasma membrane, and long-term regulation (days) through an increase in AQP2 gene expression. Mutations in this channel are associated with nephrogenic diabetes insipidus, which can be either autosomal dominant or recessive. Lithium, which is often used to treat bipolar disorder, can cause acquired diabetes insipidus by decreasing the expression of the AQP2 gene. This can result in debilitating increases in the rate of urine production. The expression of the AQP2 gene is increased during conditions associated with water retention such as pregnancy and congestive heart failure.
[edit] Aquaporins 3 and 4
These aquaporins are found in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells. In kidney, AQP3 gene expression is regulated by vasopressin (ADH), whereas AQP4 is constitutively expressed. AQP4 is expressed in astrocytes and are upregulated by direct insult to the central nervous system.
[edit] Aquaporins in mammals
Water crosses the cell membrane by either diffusing through the phospholipid bilayer or by passing through special water channels called aquaporins. More than 10 mammalian aquaporins have so far been identified, but the existence of many more is suspected. Most aquaporins appear to be exclusive water channels that will not allow permeation of ions or other small molecules. Some aquaporins - known as aquaglyceroporins - transport water plus glycerol and a few other small molecules.
Aquaporins play a key role in control of water excretion by the kidney. Vasopressin (also known as "antidiuretic hormone") is a circulating peptide that regulates aquaporin-2 to result in variable and tightly regulated water excretion. When vasopressin levels rise in the blood, the collecting duct cells in the kidneys bind more vasopressin, initiating a complex signaling process, which results in movement of aquaporin-2-containing intracellular vesicles to the plasma membrane. These vesicles fuse with the plasma membrane, thus increasing the water permeability of the cells and allowing increased return of water from the nascent urine to the blood. When vasopressin levels in the blood fall, the aquaporin-2 is retrieved by endocytosis into intracellular storage sites. The removal of aquaporin-2 from the plasma membrane lowers the water permeability of the collecting duct cells, causing more water to be retained in the excreted urine.
[edit] Aquaporins in plants
In plants water is taken up from the soil through the roots, where it passes from the cortex into the vascular tissues. There are two routes for water to flow in these tissues, known as the; apoplastic and symplastic pathways. The presence of aquaporins in the cell membranes seems to serve to facilitate the transcellular symplastic pathway for water transport. When plant roots are exposed to mercuric chloride, which is known to inhibit aquaporins, the flow of water is greatly reduced while the flow of ions is not, supporting the view that there exists a mechanism for water transport independent of the transport of ions; aquaporins.
Aquaporins in plants are seperated into four main homologous subfamilies, or groups,
- Plasma membrane Intrinsic Protein (PIP)
- Tonoplast Intrinsic Protein (TIP)
- Nodulin-26 like Intrinsic Protein (NIP)
- Small basic Intrinsic Protein (SIP)
These four subfamilies have continued to be broken up into smaller evolutionary subgroups that are directly related to their DNA sequence specificity. 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 pore plant growth and even death of the plant.
[edit] Gating of Plant Aquaporins
The gating of aquaporins is carried out to stop the flow of water through the pore of the protein. This may be carried out for a number of reasons, i.e. plant contains low amounts of cellular water due to drought. The gating of an aquaporin is carried out by an interaction between a gating mechanism and the aquaporin which causes a 3D change in the protien so that it blocks the pore and thus disallowing the flow of water through the pore. In plants it has been seen that their are at least two forms of aquaporin gating. These are gating by the dephosphorylation of certain serine residues, which has been linked as a response to drought, and the protonation of specific histidine residues in response to flooding. The phosphorylation of an aquaporin has also been linked to the opening and closing of a plant in response to temperature.
[edit] PIPs
Plasma membrane intrinsic proteins are found, as their name suggests in the plasma membrane of plant cells. There are two PIP subgroups, PIP1 and PIP2, due to the distinct differences in their peptide sequence. PIP1s commonly have lower water channel activity than PIP2s although it is not understood why. Also not understood, but the water channel activity of PIP1s has been seen to increase when in the tetramer form with PIP2s.
[edit] Aquaporins and Disease
There have been two clear examples of diseases identified as resulting from mutations 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.
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).
[edit] References
- Beitz, Eric. Aquaporins as potential drug targets. Retrieved on 2006-08-08.
- Peter Agre (2006). "The aquaporin water channels". PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY 3 (1): 5-13. PMID 16493146.
