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  1. 1. Aquaporins
  2. 2. Introduction The aquaporins (AQPs) are a family of small membrane-spanning proteins (monomer size ∼30 kDa) that are expressed at plasma membranes in many cells types involved in fluid transport.
  3. 3. Structure  Basic features of aquaporin structure have been defined using mutagenesis, epitope tagging, and spectroscopic and freeze- fracture electron microscopy methods.  Aquaporins appear to assemble in membranes as homotetramers in which each monomer, consisting of six membrane-spanning α-helical domains with cytoplasmically oriented amino and carboxy termini.
  4. 4. NPA DOMAIN  The two highly conserved NPA motifs are the most important structural domains that play a crucial role in water-selective permeation in aquaporin water channels.  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.
  5. 5. AR/R SELECTIVITY FILTER 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.
  6. 6. Functions of aquaporin  Aquaporins are "the plumbing system for cells," .  Aquaporins selectively conduct water molecules in and out of the cell, while preventing the passage of ions and other solutes. Also known as water channels, aquaporins are integral membrane pore proteins. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of the membrane's electrochemical potential.  Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.  One type of cell in which aquaporins are found is in the epithelium of the human kidney, in the distal and collecting tubules. The antidiuretic hormone (ADH) stimulates epithelial cells to incorporate aquaporins into their membranes, increasing the uptake of water from the tubule into the cells, and therefore increasing the reabsorption of water into the body.
  7. 7.  The gating of aquaporins is necessary to keep cells hydrated during periods of drought. The mechanism in some aquaporins involves the dephosphorylation of certain serine residues, causing the protein to change shape. This change in shape causes the tunnel of the protein to close and not allow any water to pass through.  In oocytes it transport glycerol and to some extent urea, along with water.
  8. 8. AQUAPORINS AS TARGETS FOR DRUG DISCOVERY  AQPs mediate water movement into the antral follicle and play important roles in follicle development.  AQPs are known to be involved in the early stage of spermatogenesis, in the secretion of tubule liquid and in the concentration and storage of spermatozoa.  AQPs take part in the processes of fertilization, blastocyst formation (as the pathway for transtrophoectodermal water movement during cavitation) and implantation.
  9. 9. Importance of Aquaporins  Aquaporins are known to play a big role in various aspects of normal body function.  Many mammalian AQPs, including AQP1, AQP2, AQP4, AQP5 and AQP8, function primarily as bidirectional water-selective transporters.  It is seen that most, if not all, significant biological functions of the mammalian AQPs, can be attributed to AQP facilitated water and/or glycerol transport.
  10. 10. AQPs in epithelial fluid transport A major role of epithelial cells is the transport of fluid across tissue barriers. Certain epithelia carry out what has been called ‘active near- isosmolar’ fluid transport, such as fluid absorption by kidney proximal tubule and fluid secretion by salivary gland acinar epithelium. Active trans-epithelial fluid transport involves the generation of an osmotic gradient by active solute transport, which drives osmotic water transport. The high trans-epithelial water permeability conferred by AQPs, increases net fluid transport.
  11. 11. Aquaporins in the Brain  AQP4 is thought to be involved in brain swelling. But it is the astrocytes rather than epithelial cells that are involved.  AQP4 is also involved in neural signalling. AQPs are expressed in electrically excitable tissues in supportive cells adjacent to excitable cells. that AQP4-dependent water permeability enhances K+ transport by a ‘pseudo- solvent drag’ mechanism. Neuro-excitation involves ion buffering in the ECS, which is the small aqueous volume surrounding cells. Excess K+ released by neurons during excitation is taken up and ‘siphoned’ largely by astrocytes. It is postulated that AQP4- facilitated water transport in astrocytes in the brain is an important determinant of both water and ion movement between cells and the ECS during neuroexcitation.
  12. 12. Other Uses of Aquaporins  Certain types of AQPs are involved in cell migration. AQP-facilitated cell migration appears to be a general phenomenon relevant in angiogenesis, tumour spread, wound healing and immune cell chemotaxis.  Recent studies have indicated roles for aquaporins in skin hydration. The channels involved in this process are AQP3 and AQP7.  AQP3 is also involved in cell proliferation.  AQP7 is found to be involved in fat metabolism.
  13. 13. Aquaporinopathies  Aquaporinopathies are human aquaporin diseases cased by mutations in aquaporin structure. These diseases are extremely rare.  One of the most common aquaporinopathy is the one caused by mutations in AQP2 which cause non-X-linked Nephrogenic Diabetes Insipidus (NDI). The incidence of NDI caused by AQP2 mutations is fewer than one in 20 million births.  Mutations in AQP0 in lens fiber cause congenital cataracts by a mechanism that is speculated to involve defective cell–cell adhesion rather than impaired water transport.
  14. 14. Aquaporin and it’s correlation to obesity  Recent studies indicate that Aquaporins play a major role in the incidence of obesity.  Aquaporins selectively conduct water molecules in and out of the cell, while preventing the passage of ions and other solutes, also known as water channels.  But some of AQP, known as aquaglyceroporins, also transport other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane, depending on the size of the pore.
  15. 15.  A subset of the AQPs, the aquaglyceroporins AQP3, AQP7 and AQP9, transport both water and glycerol.  AQP7 is expressed in the plasma membrane of adipocytes.  Aquaglyceroporins, have a less-constricted pore compared with that of water-selective AQPs (diameter of 3.4 Å compared with 2.8 Å, respectively)  Also have relatively more hydrophobic residues lining the pore.  AQP9 has been suggested as an important route for hepatic glycerol uptake.
  16. 16. AQP7- null mice manifest adiposity hypertrophy reduced plasma membrane glycerol permeability cellular glycerol and triacylglycerol accumulation, and glycerol kinase up regulation
  17. 17. Recent Studies  Since its discovery Aquaporin has been found to involved in various physiological functions  In mammals Aquaporin has been shown to play an important role in urine production and water regulation .  Many disorders that are caused due to defective functioning or deficiency /absence of Aquaporin .  Many therapies that target Aquaporin have been developed  Likewise many diagnostic techniques that are based on Aquaporin have been developed
  18. 18. Clinical Significance  The primary cause of nephrogenic diabetes insipidus ( a condition characterized by excretion of large amounts of dilute urine) has been found to mutations occurring in the Aquaporin – 2 gene  Congenital cataracts in mice are caused due to mutations in Aquaporin 0 gene  Autoimmune reactions caused by Aquaporin 4 causes Devic’s disease ( an autoimmune disorder where the body’s own immune system attacks optical nerves and the spinal cord )
  19. 19. Therapeutics  The discoverers of Aquaporin, Peter Agre et al suggested that if aquaporins could be manipulated, medical problems such as fluid retention in heart disease and brain edema after stroke could be solved  Compounds like tetraethylammonium, acetazolamide and arylsulfonamides have been found to inhibit the action of Aquaporin . These compounds are undergoing clinical trials  Aquaporin can be inhibited by heavy metals like gold and mercury but these metals are highly toxic  AQP inhibitors can be useful in diuretic edamatous states that occurs after ischemic stroke and spinal cord injury and reduce brain swelling that occur in diseases like encephalitis and meningitis
  20. 20. Diagnostics  Aquaporin 4 causes an immune disorder called Devic’s disease. Antibodies specific for APQ 4 are found in patients with this disease. These antibodies can be used for accurate diagnosis of Devic’s disease  These antibodies can also be used for diagnosing diabetes insipidus . AQP’s have been found to be excreted in urine . A person suffering from diabetes insipidus will have very low amount of functional AQP’s in the urine .Hence a rapid diagnosis of this disorder is possible using this technique  These diagnostic techniques have been performed at the experimental level . More research has to done to prove the effectiveness of this technique .
  21. 21. References  A. S. Verkman, “Aquaporins at a glance”, doi: January 14, 2011. J Cell Science, 2107-2112.  Chou, C. L., Knepper, M. A., Hoek, A. N., Brown, D., Yang, B., Ma, T. and Verkman, A. S. (1999). Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaporin-1 null mice. J. Clin. Invest. 103,491 -496.  A. S. Verkman, “Aquaporins: translating bench research to human disease” , doi: 10.1242/​jeb.024125June 1, 2009 J Exp Biol 212, 1707-1715.