Why are aquaporins necessary for transporting water across the plasma membrane quizlet?

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Curr Biol. Author manuscript; available in PMC 2014 Jan 21.

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What are aquaporins?

Aquaporins (often called aquaporin water channels) are a family of small, integral membrane proteins that are expressed broadly throughout the animal and plant kingdoms. They have a similar basic structure, with aquaporin monomers consisting of six transmembrane helical segments and two short helical segments that surround cytoplasmic and extracellular vestibules connected by a narrow aqueous pore (Figure 1A). They contain several conserved motifs, including NPA sequences in their short helical segments. Aquaporin monomers assemble as tetramers in membranes, with each monomer functioning independently. Some aquaporins, such as mammalian AQP4, can further aggregate in cell membranes to form supramolecular crystalline assemblies called orthogonal arrays of particles.

Structure and cellular functions of aquaporins

(A) Membrane topography of the aquaporin monomer (left) and crystal structure (AQP1, PDB 1j4n) (side view, left; top view, right) with four water molcules (red balls) shown in aqueous pore region. Helices are labeled H1–H8. (B) Epithelial fluid secretion. High transepithelial water permeability facilitates active, near-isosmolar fluid secretion in exocrine glands. (C) Cell migration. AQP-facilitated cell migration involves water entry into protruding lamellipodia in migrating cells. (D) Skin hydration. AQP3 maintains high levels of glycerol in the stratum corneum; glycerol acts as a humectant to retain water. (E) Adipocyte metabolism. AQP7 facilitates glycerol exit from adipocytes, preventing intracellular glycerol and triglyceride accumulation. AQP, aquaporin; TG, triglyceride; FFA, free fatty acid. (Panels B–E adapted from Verkman, A.S. (2011). Aquaporins at a glance. J. Cell Sci. 124, 2107–2112.)

What do aquaporins do at the molecular level?

The primary function of most aquaporins is to transport water across cell membranes in response to osmotic gradients created by active solute transport. Because the water transport capacity of aquaporin monomers is low, membranes often contain a high density of aquaporins, up to 10,000 per square micron, to increase water permeability substantially above that in the absence of aquaporins. Molecular dynamics simulations suggest that steric factors and electrostatic interactions in the aqueous pore are responsible for the selectivity of aquaporins for water. A subset of aquaporins, called aquaglyceroporins also transport glycerol. The pore diameter of the aquaglyceroporins is slightly greater than that of the water-selective aquaporins, and the pore is lined by relatively hydrophobic residues compared with the pore of a water-selective aquaporin. In addition to water and glycerol, there is evidence, some of which is controversial, that some aquaporins pass gases (CO2, NH3, NO, O2), various small solutes such as H2O2 and arsenite, and even ions (K+, Cl-). Non-transporting functions for some aquaporins have also been suggested, such as cell–cell adhesion, membrane polarization and regulation of interacting proteins, such as ion channels.

Why do some membranes need high water or glycerol permeability?

Most cells do not express aquaporins. Virtually all biological membranes are reasonably water permeable as a consequence of water diffusion though membrane lipids, such that cell volume equilibrates in minutes or less in response to an osmotic gradient. So then why should high membrane water permeability be needed in some cells? One example is fluid secretion and absorption across epithelial cell layers, such as in kidney tubules and exocrine glands, where normal kidney function and secretion of bodily fluids, such as saliva, require high, aquaporin-facilitated transepithelial water permeability. High water permeability also facilitates water movement across fluid–tissue barriers, such as between blood and brain parenchyma across the blood–brain barrier. Other cellular and tissue functions of aquaporin water transport, and of aquaglyceroporin-facilitated glycerol transport, are not obvious a priori.

Where are aquaporins expressed?

The mammalian aquaporins, which number about a dozen, are expressed in many cell types involved in fluid transport, including epithelia and endothelia in kidney, lung, exocrine glands, eye and gastrointestinal organs. However, aquaporins are also expressed in cells that do not have an obvious role in fluid transport, such as erythrocytes and some leukocytes, adipocytes and skeletal muscle. Aquaporins are also expressed in astrocytes throughout the central nervous system, and in supportive cells (but not electrically excitable cells) in sensory organs such as retinal Müller cells. In the eye, aquaporins are expressed in cornea, lens and ciliary epithelium. The tissue distribution of mammalian aquaporins provided initial clues about their cell and organ functions, though many of the initial guesses have not been confirmed in phenotype studies on aquaporin knockout mice.

What about aquaporins in plants and lower organisms?

Aquaporins are expressed in various plants and microbes, including bacteria and yeast. A large number of plant aquaporins have been identified, called PIPs (plasma membrane intrinsic proteins) and TIPs (tonoplast intrinsic proteins) for their cellular expression patterns. Deletion studies have elucidated a variety of interesting roles for aquaporins in plants, including transpiration, metabolism and reproduction, which are important in plant adaptation to various environmental stresses. Though aquaporins are also expressed in some microbes, deletion studies have not revealed any clear phenotype, though there is suggestive evidence that aquaporins may be protective in freeze–thaw stress, perhaps to maintain the water permeability of cell membranes at low temperature. The high surface-to-volume ratio of microbes predicts rapid osmotic equilibration, making aquaporins unnecessary for most functions, such as osmoregulation.

What anticipated roles of aquaporins have been confirmed from knockout mice?

Phenotypic analysis of aquaporin knockout mice has confirmed the anticipated role of aquaporins in transepithelial fluid transport (Figure 1B). Deletion of various aquaporins in kidney tubules causes excessive urine output and impaired urinary concentrating ability. High, aquaporin-dependent water permeability is needed in the kidney proximal tubule, for near-isosmolar fluid absorption, in the thin descending limb of Henlé, for countercurrent multiplication, and in the collecting duct, for water absorption. Aquaporins also facilitate epithelial fluid secretion in salivary and airway submucosal glands, and in the choroid plexus (from which cerebrospinal fluid is secreted) and ciliary epithelium (from which ocular aqueous fluid is secreted). There is an important caveat, however: aquaporins are required for transepithelial fluid transport when fluid transport rate (per epithelial surface area) is very high, as in proximal tubule and salivary gland. Though aquaporins are expressed and functional in lung, intestinal and sweat gland epithelia, they do not appear to have a significant physiological role.

What are some less obvious roles of aquaporin-facilitated water transport?

An unanticipated role of aquaporins is in cell migration. AQP1 deletion in mice impairs angiogenesis as a consequence of a reduction in the migration speed of microvascular endothelial cells. Aquaporin-dependent migration has been found in a wide variety of cell types. Biophysical studies suggest that aquaporin polarization to the leading edge of migrating cells facilitates water influx during lamellipodial extension (Figure 1C). In contrast to transepithelial fluid transport, where aquaporins facilitate water movement across cell layers, aquaporins in migrating cells facilitate local, transient water transport. Another unanticipated role of an aquaporin is in neuroexcitation: deletion of AQP4 impairs neurosensory signaling and alters seizure and cortical spreading depression dynamics. Although the mechanism has not been fully resolved, it appears that AQP4-facilitated water transport is needed for rapid changes in extracellular space volume and K+ concentration, and that loss of AQP4 leads to delayed K+ reuptake following neuroexcitation. Other unexpected roles of water-selective aquaporins include their involvement in corneal and lens transparency, brain and spinal cord swelling, neuroinflammation and pain.

What about glycerol transport by aquaglyceroporins?

The mammalian aquaglyceroporins include AQP3, AQP7 and AQP9. AQP3 is expressed in the basal layer of proliferating keratinocytes in the epidermis (Figure 1D). Mice lacking AQP3 have reduced skin hydration and elasticity, which is due to impaired glycerol transport from the blood to the epidermis and consequent reduced glycerol content in the epidermis and stratum corneum. Reduced glycerol impairs skin hydration and elasticity, as glycerol is a major humectant (water-retaining osmolyte). Reduced glycerol also impairs epidermal proliferation, as glycerol is an important epidermal cell metabolite involved in ATP generation and membrane lipid biosynthesis. There has been considerable interest in AQP3 in the cosmetic industry, with marketed products claiming to increase AQP3 expression. Recent studies have suggested an important role of AQP3 in macrophage and T-lymphocyte function, perhaps involving AQP3-facilitated H2O2 transport. Another intriguing observation, made in mice lacking AQP7, is progressive obesity with adipocyte hypertrophy, which appears to be a consequence of impaired glycerol efflux from adipocytes. Reduced plasma membrane glycerol permeability resulting from AQP7 deficiency leads to intracellular accumulation of glycerol and triglycerides (Figure 1E), suggesting the possibility of AQP7 upregulation to reduce fat mass in obesity. Finally, AQP9 expression in hepatocytes has been proposed to facilitate hepatic glycerol uptake, though the significance of hepatic glycerol uptake in human metabolism is unclear.

What about aquaporins in cancer?

Provocative data implicate aquaporins in some cancers. A large descriptive literature reports strong expression of aquaporins in brain, skin, gastrointestinal, lung and other cancers, often with correlations between aquaporin expression and tumor grade. Tumors often overexpress aquaporin(s) found in the cell type of origin, such as AQP4 in astrocyte-derived glioblastomas, although sometimes tumor cells express aquaporins that are not seen in the cells of origin. Several mechanisms have been proposed that link aquaporin expression with cancer. AQP1 is strongly expressed in tumor microvessels, and its deletion in mice reduces tumor angiogenesis. Expression of various aquaporins in tumor cells increases their migration and metastatic potential in cell culture and animal models. AQP3 increases the proliferation of various tumor cells, and mice lacking AQP3 are highly resistant to skin cancer. Though many questions remain to be addressed, aquaporin inhibition for cancer therapy is an intriguing idea.

Are any human diseases caused by aquaporin abnormalities?

One rare hereditary disease is caused by loss-of-function mutations in AQP2, a water channel expressed in the kidney collecting duct. AQP2 facilitates transepithelial water absorption in the kidney collecting duct in response to antidiuretic hormone, and this process involves the exocytic insertion of AQP2-containing vesicles into the apical membrane of the cell. Mutations in AQP2 that interfere with its cellular trafficking or water transport function result in the disease nephrogenic diabetes insipidus, in which large volumes of dilute urine, sometimes exceeding 30 liters per day, are excreted. Mutations in AQP0 (originally called ‘major intrinsic protein of lens fiber’) are associated with congenital cataracts; however, the mechanism of cataractogenesis is not known as it is unclear whether the main function of AQP0 is in lens structure or the water permeability of lens fiber cells. Loss-of-function mutations in several other aquaporins have been identified in a handful of individuals, although none appears to be associated with significant disease. An interesting autoimmune neurological disease, neuromyelitis optica, is caused by autoantibodies directed against extracellular epitopes on AQP4. Autoantibody binding causes complement- and cell-mediated astrocyte cytotoxicity, which leads to inflammation, with cytokine release, leukocyte infiltration and blood–brain barrier disruption. The inflammatory demyelinating lesions in the spinal cord and optic nerve lead to paralysis and blindness. So far other aquaporin-based autoimmune diseases have not been discovered.

What about aquaporin-based therapy for human diseases?

There is considerable interest though little progress in aquaporin-based therapeutics. Data from cell and animal models provide a compelling rationale for the development of aquaporin modulators as therapeutics: AQP1 inhibitors are predicted to have utility in diuretic-refractory edema, tumor angiogenesis and glaucoma; AQP4 inhibitors in some forms of brain edema and injury; and AQP3 inhibitors in some cancers. Upregulators of the expression of some aquaporins have potential therapeutic utility for obesity, wound healing and spinal cord injury. Certain heavy metal (mercury, gold) containing compounds that react non-specifically with protein sulfhydryls inhibit the water permeability of some aquaporins. However, the identification of nontoxic, small-molecule aquaporin inhibitors has not been possible, perhaps for a combination of reasons, including challenges in function-based screening assays and the intrinsic refractoriness of aquaporins to drug discovery (termed non-druggability). One area of recent progress is in AQP4-based therapeutics for neuromyelitis optica. The idea is to block the binding of pathogenic autoantibodies to astrocyte AQP4, which may provide a targeted, non-immunosuppressive approach to block the disease-initiating event in neuromyelitis optica. One approach has been the engineering of a non-pathogenic, tight-binding anti-AQP4 antibody (‘aquaporumab’) that competes with pathogenic autoantibodies; another approach has been the identification, by high-throughput screening, of small-molecule blockers of the autoantibody–AQP4 interaction.

What's next?

There remain significant gaps in our knowledge about the cellular mechanisms of certain aquaporin functions, such as aquaporin-facilitated cell migration, cell proliferation, and neuroexcitatory phenomena. Though much of the low-hanging fruit in the aquaporin field has been picked and digested, as in areas of aquaporin protein structure and phenotypic analysis of knockout mice, new discoveries and ideas continue to emerge. Compelling recent data warrant further investigation of aquaporins in cancer, immune cell function and obesity. Lastly, notwithstanding the challenges and limited progress in the identification of aquaporin inhibitors, broad opportunities remain in aquaporin-based therapeutics.

Where can I find out more?

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  • Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012;11:535–544. [PMC free article] [PubMed] [Google Scholar]
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Why are aquaporins necessary for transporting water across the plasma membrane?

Because of the slow diffusion of water across the lipid bilayer, aquaporins effectively increase the overall rate of water movement across the cell membrane.

What are aquaporins Why are they necessary?

Aquaporins are proteins made of amino acids that form a narrow pore in the cell membrane for water to pass through. They are important for regulating water balance in plants, animals, and even bacteria. Secretory tissues in humans, such as glands, rely on aquaporins to secrete properly.

What is the function of aquaporins Why are they necessary quizlet?

Aquaporins are a special type of transport protein that allow rapid diffusion of water in and out of certain cells.

What are aquaporin What is the role of aquaporin in water transport?

Aquaporins (AQPs) are a family of small transmembrane proteins that mainly facilitate water transport across plasma membranes through an aqueous pore Verkman (2008). These proteins are expressed ubiquitously in humans, animals–vertebrates and invertebrates, plants and microorganisms Agre et al (2002).

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