Potassium channel Kir4.1 macromolecular complex in retinal glial cells

Connors, Nathan C.; Kofuji, Paulo

doi:10.1002/glia.20271

Cited by 80 publications

(72 citation statements)

References 45 publications

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“…This latter clustered on glial membranes only in the presence of Dp71. 48 In fact, in the retina of Dp71 knockout mice, both AQP4 and Kir 4.1 expression levels are decreased and mislocated around blood vessels. 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.…”

Section: Discussionmentioning

confidence: 99%

“…48 In fact, in the retina of Dp71 knockout mice, both AQP4 and Kir 4.1 expression levels are decreased and mislocated around blood vessels. 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%

“…46 The dystrophin isoform Dp71 is localized in the perivascular glial endfeet, in which it is involved in BBB maturation 39,47 and in the clustering of the AQP4 water channel on the astrocyte glial membranes. 48 Glial DAPs, laminin and agrin in mdx mice B Nico et al AQP4 controls BBB functioning and integrity, because its expression parallels BBB development and is altered after BBB damage. 7,49 AQP4 expression on the perivascular processes of astrocytes is correlated to the ability of astrocytes to remove K þ excess from the extracellular clefts by active and passive uptake and K þ flux.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Further evidence for a possible coupling of K + and water transport in perivascular astrocytes stems from the observation that Aqp4 and Kir4.1 channels are interconnected via a dystrophin-glycoprotein complex (DGC) at the plasma membrane (PM) of perivascular retinal glia cells (Connors and Kofuji, 2006) and astrocytes (Guadagno and Moukhles, 2004;Hibino et al, 2004;Kofuji and Newman, 2004). The co-localization of Kir4.1, and Aqp4 to one PM complex in astrocytic end-feet, at capillaries, and at the pia further supports the notion that the regulation of extracellular potassium levels is coupled with water transport (Hibino et al, 2004;Nagelhus et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc spf mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otc spf /GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/ Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport.Since, ions can permeate water and K + -channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.

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“…The polarized distributions of Kir4.1 and AQP4 suggest that they facilitate 'buffering' of K + , which is produced during neuronal activity, from inner retina to the vitreous through the Müller cells, by a process known as 'potassium siphoning'. Immunoelectron microscopy has shown colocalization of AQP4 and Kir4.1 (Nagelhus, 1999), and immunoprecipitation suggested AQP4-Kir4.1 interaction, possibly as a part of a macromolecular complex that includes α-syntrophin and dystrophin (Connors et al, 2004;Connors and Kofuji, 2006). Based on this indirect evidence, a functional interaction between AQP4 and Kir4.1 K + channel has been inferred and proposed to account for the various neural signaling phenotypes associated with AQP4 deficiency.…”

Section: Light-neural Signal Transduction and K + Bufferingmentioning

confidence: 98%

Functions of aquaporins in the eye

Verkman

Ruiz-Ederra

Levin

2008

Progress in Retinal and Eye Research

171

117

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The aquaporins (AQPs) are integral membrane proteins whose main function is to transport water across cell membranes in response to osmotic gradients. At the ocular surface, AQP1 is expressed in corneal endothelium, AQP3 and AQP5 in corneal epithelium, and AQP3 in conjunctival epithelium. AQPs are also expressed in lens fiber cells (AQP0), lens epithelium (AQP1), ciliary epithelium (AQP1, AQP4) and retinal Müller cells (AQP4). Mutations in AQP0 produce congenital cataracts in humans. Analysis of knockout mice lacking individual AQPs suggests their involvement in maintenance of corneal and lens transparency, corneal epithelial repair, intraocular pressure regulation, retinal signal transduction and retinal swelling following injury. The mouse phenotype findings implicate AQPs as potential drug targets for therapy of elevated intraocular pressure and ocular disorders involving the cornea, lens and retina. However, much research remains in defining cell-level mechanisms for the ocular AQP functions, in establishing the relevance to human eye disease of conclusions from knockout mice, and in developing AQPmodulating drugs.

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Potassium channel Kir4.1 macromolecular complex in retinal glial cells

Cited by 80 publications

References 45 publications

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

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

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Functions of aquaporins in the eye

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