Departments of Medicine and Physiology, Cardiovascular Research Institute, Room 1246, Box 0521 University of California San Francisco, San Francisco, CA 94143-0521, USA
(e-mail: verkman{at}itsa.ucsf.edu)
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Summary |
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Key words: Aquaporin, Water channel, Epithelia, Cell migration, Adipocyte, Brain swelling, Epidermis, Gland, Angiogenesis
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Structure, function and cellular expression of aquaporins |
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AQP1, AQP2, AQP4, AQP5 and AQP8 are primarily water selective (Table 1), whereas AQP3, AQP7, AQP9 and AQP10 (called `aquaglyceroporins') also transport glycerol and possibly other small solutes in the case of AQP9 (reviewed by Agre et al., 2002; Yasui, 2004
). Molecular-dynamic simulations based on the AQP1 crystal structure suggest tortuous, single-file passage of water through a narrow <0.3 nm pore, in which steric and electrostatic factors prevent transport of protons and other small molecules (Tajkhorshid et al., 2002
). There are reports that AQP1 transports cations (Anthony et al., 2000
), AQP7 and AQP9 transport heavy metal salts such as arsenite (Liu et al., 2002
), and AQP6 transports chloride at low pH (Yasui et al., 1999
), although the significance of these observations is unclear and they await verification by other labs. Reports have suggested that AQP1 transports gases such as carbon dioxide (Cooper and Boron, 1998
) and ammonia (Nakhoul et al., 2001
), although data from others labs (reviewed by Verkman, 2002
) lead to the conclusion that AQP1-dependent gas transport, if it occurs, is not biologically significant. With the exception of vasopressin-regulated AQP2, AQPs are subject primarily to transcriptional-level rather than short-term regulation. However, there is evidence, albeit controversial, for regulated targeting of AQPs in the liver (Marinelli et al., 1999
) and salivary glands (Gresz et al., 2004
) and for regulation of AQP4 function by protein kinase C (PKC)-dependent phosphorylation (Zelenina et al., 2002
). The transport function of many AQPs can be inhibited by nonspecific, mercurial sulfhydral-reactive compounds, such as HgCl2; there is considerable interest in the identification of non-toxic, AQP-selective inhibitors (Castle, 2005
; Verkman, 2001
).
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Epithelial fluid transport |
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The message from the kidney phenotype data is that AQPs can be important in rapid, osmotically driven water transport, as in the collecting duct, and in active, `near-isosmolar' fluid transport, as in the proximal tubule. In the collecting duct, water is osmotically extracted from the tubule lumen into the hypertonic medullary interstitium of the kidney. If the water permeability of the collecting duct is low then the excreted urine is not concentrated, because of inadequate extraction of free water from the luminal fluid (Fig. 2A). In the proximal tubule, salt is pumped actively from the tubule lumen into a basal-lateral `third compartment', which is mildly hypertonic compared with the luminal fluid. The mild hypertonicity drives water across the highly water permeable plasma membranes of proximal tubule cells. The reduced water permeability produced by AQP1 deficiency results in impaired fluid absorption.
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Brain and corneal swelling |
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AQP-dependent edema is also important in the cornea. Maintenance of corneal transparency requires precise regulation of stromal water content. This is believed to be controlled primarily by the transport of salt and water by the corneal endothelium (facing the aqueous fluid space), where AQP1 is expressed. Interestingly, corneal thickness is reduced 20% in AQP1-null mice (Thiagarajah and Verkman, 2002
). After exposure of the corneal endothelial surface to hypotonic saline, the rate of corneal swelling is reduced
80% in the AQP1 knockouts. Although baseline corneal transparency is not abnormal in these mice, their recovery of corneal transparency and thickness after hypotonic swelling is remarkably delayed. This implicates AQP1 in active extrusion of fluid from the corneal stroma across the corneal endothelium. However, the precise dynamics of salt and water transport under stress remains to be established.
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Cell migration |
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Analysis of intrinsic endothelial cell functions in cultured endothelia indicates that cell migration towards a chemoattractant (fetal bovine serum) in Boyden chamber assays is significantly slowed in AQP1-deficient endothelial cells. Even larger differences are apparent in cell `invasion' assays in which cells migrate through a Matrigel layer.
AQP-dependent water transport could account for the impaired migration in AQP1-deficient mice. Cell migration involves transient formation of membrane protrusions (lamellipodia and membrane ruffles) at the leading edge of the cell. This is thought to require rapid local changes in ion fluxes and cell volume, which are probably accompanied by rapid transmembrane water movement (Condeelis, 1993; Lauffenburger and Horwitz, 1996
). Exogenously expressed AQP1 or AQP4 enhances migration of AQP-null CHO and FRT epithelial cells through a porous filter as well as wound closure. This indicates the effect is not AQP or cell-type specific. Interestingly in many cells, AQP1 localizes to the leading edge of the cell membrane (Fig. 4A), which has also been found for several transporters involved in migration, including the Na+/H+ and Cl-/HCO3- exchangers, and the Na+/HCO3- cotransporter (Schwab, 2001
). Rapid time-lapse video microscopy shows that AQP1 expression produces more protrusions (lamellipodia) and a shorter mean residence time of protrusions. This suggests that AQPs accelerate cell migration by facilitating the rapid turnover of membrane protrusions at the leading edge.
Actin cleavage and ion uptake at the tip of a lamellipodium could create local osmotic gradients that drive the influx of water across the cell membrane (Fig. 4B). Water entry might then increase local hydrostatic pressure to cause cell membrane protrusion, which might create space for actin polymerization. AQPs in the region of membrane protrusions could enhance water entry and thus the dynamics of cell membrane protrusions and cell motility. Further biophysical studies are needed to test this proposed mechanism. Studies should also examine whether AQP-dependent cell migration is a general phenomenon in other biological processes besides angiogenesis, such as tumor spreading, wound healing, leukocyte chemotaxis and organ regeneration.
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Cellular roles of aquaporin-dependent glycerol transport |
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Epidermal hydration and biosynthesis
The most superficial layer of skin is the stratum corneum (SC), which consists of terminally differentiated corneocytes that originate from actively proliferating keratinocytes in the underlying epidermis (Fig. 5A). Hydration of the SC is an important determinant of the appearance and physical properties of the skin, and depends on several factors, including the external humidity, skin structure, lipid/protein composition, barrier properties, and the concentration of water-retaining `humectants' such as free amino acids, ions and other small solutes. AQP3 is expressed strongly in the basal layer of keratinocytes in mammalian skin (Fig. 5B). Hairless mice (frequently used for functional analysis of skin) lacking AQP3 exhibit reduced SC hydration measured by high-frequency superficial skin conductance or by 3H2O partitioning (Ma et al., 2002). In addition, they have reduced skin elasticity, delayed biosynthesis of the SC after removal by tape-stripping, and delayed wound healing (Hara et al., 2002
). Interestingly, exposure of mice to high humidity or occlusion increases SC hydration in wild-type mice, but not in AQP3-null mice, indicating that water transport through AQP3 is not a rate-limiting factor in trans-epidermal water loss. If reduced SC hydration were related to a balance between evaporative water loss from the SC and water replacement through AQP3-containing basal keratinocytes, then preventing water loss should have corrected the defect in SC hydration in the AQP3-null mice. Investigation of the mechanisms responsible for the skin phenotype in AQP3 deficiency showed reduced epidermal cell skin glycerol permeability, and reduced glycerol content in the SC and epidermis, with normal glycerol in dermis and serum. This suggests there is reduced glycerol transport from blood into the epidermis through the basal keratinocytes in the AQP3-null mice. Differences in SC structure, cell turnover, lipid profile, protein content, and the concentrations of amino acids, ions and other small solutes are not evident (Hara et al., 2002
).
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A reduced epidermal and SC glycerol content caused by lack of AQP3-facilitated glycerol transport is probably responsible for the abnormal skin phenotype in AQP3-null mice (Fig. 5C). Impaired glycerol transport into the epidermis and SC through the relatively glycerol-impermeable basal keratinocyte layer would reduce the steady-state epidermal and SC glycerol content. The reduced SC hydration and elasticity is likely to be related to the water-retaining property of glycerol, and the delayed barrier recovery and wound healing to the biosynthetic role of glycerol. Indeed, glycerol replacement by topical or systemic routes corrects each of the skin phenotype abnormalities in AQP3-null mice (Hara and Verkman, 2003). The data indicate the importance of glycerol in epidermal function and provide a rational scientific basis for the long-standing practice of including glycerol in cosmetic and medicinal skin-treatment preparations.
Adipocyte fat accumulation
A principal site of expression of AQP7 is the plasma membrane of adipocytes. AQP7-null mice attain a much greater fat mass than wild-type mice as they age (Hara-Chikuma et al., 2005). Moreover, their adipocytes are much larger by 16 weeks (Fig. 6A) and accumulate approximately threefold more glycerol and approximately twofold more triglycerides than do wild-type adipocytes. Measurements in adipocytes of comparable size from younger mice showed
65% reduction in glycerol permeability in AQP7-deficient adipocytes and slowed glycerol release from minced fat tissue. Lipolysis and lipogenesis rates are similar in wild-type and AQP7-deficient mice. The progressive triglyceride accumulation in AQP7-deficient adipocytes could be due to reduced plasma membrane glycerol permeability. This should increase the steady-state glycerol concentration in adipocytes, which would result in increased glycerol-3-phosphate and hence triglyceride biosynthesis (Fig. 6B). Adipocyte glycerol permeability may thus be a novel regulator of adipocyte size. Induction of adipocyte AQP7 expression and/or function might therefore reduce fat mass in some forms of obesity.
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Neural signal transduction |
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Other proposed cellular roles of aquaporins |
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Conclusions and perspective |
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