Implications of the Aquaporin-4 Structure on Array Formation and Cell Adhesion

Hiroaki, Yoko; Tani, Kazuhide; Kamegawa, Akiko; Gyobu, Nobuhiko; Nishikawa, Kyoji; Suzuki, Hiroshi; Walz, Thomas; Sasaki, Sei; Mitsuoka, Kaoru; Kimura, Kei; Mizoguchi, Akira; Fujiyoshi, Yoshinori

doi:10.1016/j.jmb.2005.10.081

Cited by 365 publications

(380 citation statements)

References 42 publications

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“…The more likely explanation for the presence of distinct AQP4 pools is that they correspond to OAPs of different sizes. Electron microscopy data of 2D-AQP4 crystals indicates that AQP4, like all known water channels, is organized in the membrane in tetramers (Hiroaki et al 2006) which correspond to IMPs when visualized by freeze-fracture electron microscopy. Assuming that in astrocytes the number of IMPs in each OAP is 25 (Rash et al 2004), the predicted mass of an OAP is 3 MDa, a value which is close to the size of the largest AQP4 pool found in our BN/SDS-PAGE analysis.…”

Section: Discussionmentioning

confidence: 99%

Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex

Nicchia

Cogotzi

Rossi

et al. 2008

Journal of Neurochemistry

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Altered aquaporin-4 (AQP4) expression has been reported in brain edema, tumors, muscular dystrophy, and neuromyelitis optica. However, the plasma membrane organization of AQP4 and its interaction with proteins such as the dystrophin-associated protein complex are not well understood. In this study, we used sucrose density gradient ultracentrifugation and 2D blue native/sodium dodecyl sulfate-polyacrylamide gel electrophoresis and showed the expression of several AQP4 multi-subunit complexes (pools) of different sizes, ranging from >> 1 MDa to similar to 500 kDa and containing different ratios of the 30/32 kDa AQP4 isoforms, indicative of orthogonal arrays of particles of various sizes. A high molecular weight pool co-purified with dystrophin and beta-dystroglycan and was drastically reduced in the skeletal muscle of mdx3cv mice, which have no dystrophin. The number and size of the AQP4 pools were the same in the kidney where dystrophin is not expressed, suggesting the presence of dystrophin-like proteins for their expression. We found that AQP2 is expressed only in one major pool of similar to 500 kDa, indicating that the presence of different pools is a peculiarity of AQP4 rather than a widespread feature in the AQP family. Finally, in skeletal muscle caveolin-3 did not co-purify with any AQP4 pool, indicating the absence of interaction of the two proteins and confirming that caveolae and orthogonal arrays of particles are two independent plasma membrane microdomains. These results contribute to a better understanding of AQP4 membrane organization and raise the possibility that abnormal expression of specific AQP4 pools may be found in pathological states

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Section: Discussionmentioning

confidence: 99%

Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex

Nicchia

Cogotzi

Rossi

et al. 2008

Journal of Neurochemistry

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“…It is difficult to assess the merit of the reported binding computations because of the use of a non-standard algorithm and because computational details (such as search space and energy minimization criteria) were not provided. Although not stated explicitly, the AQP4 structure data were likely those of the electron crystallography data set of Hiroaki et al 20 , with reported in-plane resolution of ~3.2 Angstroms and out-of-plane resolution of ~3.6 Angstroms. Generally, meaningful docking computations require x-ray data with resolution of ~2.5 Angstroms or better 21,22 .…”

Section: Discussionmentioning

confidence: 99%

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Yang

Zhang

Verkman

2008

Bioorganic & Medicinal Chemistry

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Inhibitors of brain glial water channel aquaporin-4 (AQP4) are of potential clinical utility, as they are predicted to modulate brain edema, neuroexcitation and glial scarring. Recently, Huber et al. (Bioorgan. Med. Chem. 2007, 17:1270 2008, in press) reported that a series of arylsulfomamides, antiepileptics, and related small molecules strongly inhibited AQP4 water transport with IC50s down to 1 μM. We retested the compounds with greatest reported potencies, including acetylsulfanilamide, acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide, phenytoin, lamotrigine and sumatriptan, in AQP4-transfected mammalian cells and primary cultures of brain glial cells, using several sensitive assays of osmotic water permeability. Contrary to the findings of Huber et al., in our studies we found no significant inhibition of AQP4 water permeability by any of the compounds at concentrations up to 100 μM.

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“…There are two isoforms of AQP4 with AQP4-M1 (323 aa) having a 22 amino acids longer N-terminus than AQP4-M23 (301 aa) (14)(15)(16). High-resolution crystal structures of AQP4 showed that the asparagine of each NPA motif forms hydrogen bonds to a water molecule in the center of the channel, which is different from AQP1 where two asparagines from both NPA motifs form hydrogen bonds to one water molecule (17)(18)(19). Some other studies showed different protein folding pathways between AQP4 and AQP1 during biogenesis (20,21).…”

Section: Introductionmentioning

confidence: 99%

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

Guan

et al. 2010

IUBMB Life

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SummaryThe two highly conserved NPA motifs (asparagine-prolinealanine, NPA) are the most important structural domains that play a crucial role in water-selective permeation in aquaporin water channels. However, the functions of NPA motifs in aquaporin (AQP) biogenesis remain largely unknown. Few AQP members with variations in NPA motifs such as AQP11 and AQP12 do not express in the plasma membrane, suggesting an important role of NPA motifs in AQP plasma membrane targeting. In this study, we examined the role of the two NPA motifs in AQP4 plasma membrane targeting by mutagenesis. We constructed a series of AQP4 mutants with NPA deletions or single amino acid substitutions in AQP4-M1 and AQP4-M23 isoforms and analyzed their expression patterns in transiently transfected FRT and COS-7 cells. Western blot analysis showed similar protein bands of all the AQP4 mutants and the wild-type AQP4. AQP4 immunofluorescence indicated that deletion of one or both NPA motifs resulted in defective plasma membrane targeting, with apparent retention in endoplasmic reticulum (ER). The A99T mutant mimicking AQP12 results in ER retention, whereas the A99C mutant mimicking AQP11 expresses normally in plasma membrane. Furthermore, the AQP4-M1 but not the M23 isoform with P98A substitution in the first NPA motif can target to the plasma membrane, indicating an interaction of Nterminal sequence of AQP4-M1 with the first NPA motif. These results suggest that NPA motifs play a key role in plasma membrane expression of AQP4 but are not involved in AQP4 protein synthesis and degradation. The NPA motifs may interact with other structural domains in the regulation of membrane trafficking during aquaporin biogenesis.

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Implications of the Aquaporin-4 Structure on Array Formation and Cell Adhesion

Cited by 365 publications

References 42 publications

Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex

Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

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