Aquaporin-4 is absent at the sarcolemma and at perivascular astrocyte endfeet in α1-syntrophin knockout mice

Yokota, Toshifumi; Miyagoe, Yuko; Hosaka, Yukio; Tsukita, Kayoko; Kameya, Shuhei; Shibuya, Seiji; Matsuda, Ryoichi; Wakayama, Yoshihiro; Takeda, Shin‐ichi

doi:10.2183/pjab.76.22

Cited by 49 publications

(61 citation statements)

References 3 publications

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“…While our work was being completed, independent studies suggested that subcellular localization of AQP4 is altered in ␣-Syn Ϫ/Ϫ skeletal muscle without a change in total expression estimated by immunoblot (24). Although we cannot explain this discrepancy, we have not been able to detect AQP4 in immunoblots of whole membranes from skeletal muscle without prior immunoprecipitation (18).…”

Section: Discussionmentioning

confidence: 81%

Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein

Neely

Amiry-Moghaddam

Ottersen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

422

428

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The Aquaporin-4 (AQP4) water channel contributes to brain water homeostasis in perivascular astrocyte endfeet where it is concentrated. We postulated that AQP4 is tethered at this site by binding of the AQP4 C terminus to the PSD95-Discs large-ZO1 (PDZ) domain of syntrophin, a component of the dystrophin protein complex. Chemical cross-linking and coimmunoprecipitations from brain demonstrated AQP4 in association with the complex, including dystrophin, ␤-dystroglycan, and syntrophin. AQP4 expression was studied in brain and skeletal muscle of mice lacking ␣-syntrophin (␣-Syn ؊/؊ ). The total level of AQP4 expression appears normal in brains of ␣-Syn ؊/؊ mice, but the polarized subcellular localization is reversed. High-resolution immunogold analyses revealed that AQP4 expression is markedly reduced in astrocyte endfeet membranes adjacent to blood vessels in cerebellum and cerebral cortex of ␣-Syn ؊/؊ mice, but is present at higher than normal levels in membranes facing neuropil. In contrast, AQP4 is virtually absent from skeletal muscle in ␣-Syn ؊/؊ mice. Deletion of the PDZ-binding consensus (Ser-Ser-Val) at the AQP4 C terminus similarly reduced expression in transfected cell lines, and pulse-chase labeling demonstrated an increased degradation rate. These results demonstrate that perivascular localization of AQP4 in brain requires ␣-Syn, and stability of AQP4 in the membrane is increased by the C-terminal PDZ-binding motif.

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Section: Discussionmentioning

confidence: 81%

Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein

Neely

Amiry-Moghaddam

Ottersen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

422

428

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“…51 AQP4 is also associated with Kir 4.1 and with other components of DAPs, 28,48 such as a-syntrophin, which anchored AQP4 in a polarized way on the astrocytic membranes facing the vessels by interaction of its PDZ domain with the C-terminal SSV residues of AQP4. 13,52,53 Furthermore, a-syntrophin-null mice showed AQP4 reduction and redistribution and delayed K þ clearance, 13,31 suggesting that a correct link between AQP4 proteins and DAPs is necessary for an efficient K þ removal.…”

Section: Discussionmentioning

confidence: 99%

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Nico

Tamma

Annese

et al. 2010

Laboratory Investigation

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In this study, we investigated the involvement of dystrophin-associated proteins (DAPs) and their relationship with the perivascular basement membrane in the brains of mdx mice and controls at the age of 2 months. We analyzed (1) the expression of glial DAPs a-b-dystroglycan (DG), a-syntrophin, aquaporin-4 (AQP4) water channel, Kir 4.1 and dystrophin isoform (Dp71) by immunocytochemistry, laser confocal microscopy, immunogold electron microscopy, immunoblotting and RT-PCR; (2) the ultrastructure of the basement membrane and expression of laminin and agrin; and (3) the dual immunofluorescence colocalization of AQP4/a-b-DG, and of Kir 4.1/agrin. The following results were observed in mdx brain as compared with controls: (1) a significant reduction in protein content and mRNA expression of DAPs; (2) ultrastructurally, a thickened and discontinuous appearance of the basement membrane and a significant reduction in laminin and agrin; and (3) a molecular rearrangment of a-b-DG, coupled with a parallel loss of agrin and Kir 4.1 on basement membrane and glial endfeet. These data indicate that in mdx brain the deficiency in dystrophin and dystrophin isoform (Dp71) is coupled with a reduction of DAP components, coupled with an altered anchoring to the basement membrane. The blood-brain barrier (BBB) controls the selective exchanges between blood and neuropil by specific molecular and structural features of its vascular and perivascular components, including endothelial cells, pericytes, glial endfeet and basement membrane. 1-3 Glial cells have a key role in the control of BBB development and integrity. They express in a polarized way, on their perivascular endfeet, carrier membranes and channel proteins, including aquaporin-4 (AQP4) water channel and potassium channel Kir 4.1, which are responsible for the water flow rate and spatial K þ buffering control. [4][5][6][7][8][9] In the retina, AQP4 colocalizes with Kir 4.1, 9-11 suggesting a tight cooperation between the water flux and K þ siphoning generated by neuronal activity at the BBB interfaces. Moreover, AQP4 and Kir 4.1 rearrangement has been described in BBB alterations, coupled with cytotoxic edema and K þ -delayed buffering capacity. 12,13 AQP4 has a crucial role in the regulation of the interactions occurring between endothelial and glial cells and between glial cells and the extracellular matrix components. AQP4 is a component of the orthogonal aggregate particles (OAPs), demonstrated by freeze fracturing on the ependimoglial membrane and perivascular glial endfeet, 14 the development of which occurs in parallel with AQP4 glial endfeet expression and BBB maturation. 7 Moreover, OAPs contain AQP4 associated with Kir 4.1 12 and their polarized distribution on the glial endfeet seems to be dependent by the presence of the perivascular basement membrane. 15 AQP4 controls BBB functioning, modifying

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“…Whether the organization of AQP4 in distinct pools results from the interaction of AQP4 with different binding partners remains unknown. Studies on dystrophin-deficient animal models mdx mice (Frigeri et al 1998Vajda et al 2004) and asyntrophin null mice (Yokota et al 2000;Neely et al 2001;Bragg et al 2006) suggested an interaction of AQP4 with dystrophin and/or components of the dystrophin-glycoprotein complex (DGC). However, none of the DGC proteins have been shown to directly interact with AQP4.…”

mentioning

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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Aquaporin-4 is absent at the sarcolemma and at perivascular astrocyte endfeet in α1-syntrophin knockout mice

Cited by 49 publications

References 3 publications

Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein

Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

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

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