Proliferative gliosis causes mislocation and inactivation of inwardly rectifying K+ (Kir) channels in rabbit retinal glial cells

Ulbricht, Elke; Pannicke, Thomas; Hollborn, Margrit; Raap, Maik; Goczalik, Iwona; Iandiev, Ianors; Härtig, Wolfgang; Uhlmann, Susann; Wiedemann, Peter; Reichenbach, Andreas; Bringmann, Andreas; Francke, Mike

doi:10.1016/j.exer.2007.11.002

Cited by 25 publications

(22 citation statements)

References 32 publications

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“…Immunoblot analysis demonstrated robust bands as predicted according to the momomer subunit molecular weights, 42 kDa for Kir4.1 and 48 kDa for Kir5.1. In addition, bands for Kir4.1 were indicated at 80 and 160 kDa, which corresponds to the heteromeric and homo-tetrameric channel as observed previously in the brain and retina (Kofuji et al 2000; Ulbricht et al 2008). Furthermore, bands were detected at 70 kDa for Kir5.1, which were more enriched in the optic nerve plasma membrane fraction, and are consistent with previous findings indicating the ion channel is regulated by glycosylation (Ishii et al 2003).…”

Section: Discussionsupporting

confidence: 73%

Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS

et al. 2016

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The inwardly rectifying K+ channel subtype Kir5.1 is only functional as a heteromeric channel with Kir4.1. In the CNS, Kir4.1 is localised to astrocytes and is the molecular basis of their strongly negative membrane potential. Oligodendrocytes are the specialised myelinating glia of the CNS and their resting membrane potential provides the driving force for ion and water transport that is essential for myelination. However, little is known about the ion channel profile of mature myelinating oligodendrocytes. Here, we identify for the first time colocalization of Kir5.1 with Kir4.1 in oligodendrocytes in white matter. Immunolocalization with membrane-bound Na+/K+-ATPase and western blot of the plasma membrane fraction of the optic nerve, a typical CNS white matter tract containing axons and the oligodendrocytes that myelinate them, demonstrates that Kir4.1 and Kir5.1 are colocalized on oligodendrocyte cell membranes. Co-immunoprecipitation provides evidence that oligodendrocytes and astrocytes express a combination of homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. Genetic knock-out and shRNA to ablate Kir4.1 indicates plasmalemmal expression of Kir5.1 in glia is largely dependent on Kir4.1 and the plasmalemmal anchoring protein PSD-95. The results demonstrate that, in addition to astrocytes, oligodendrocytes express both homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. In astrocytes, these channels are essential to their key functions of K+ uptake and CO2/H+ chemosensation. We propose Kir4.1/Kir5.1 channels have equivalent functions in oligodendrocytes, maintaining myelin integrity in the face of large ionic shifts associated with action potential propagation along myelinated axons.

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Section: Discussionsupporting

confidence: 73%

Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS

et al. 2016

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“…Notably, the DGC has been implicated in targeting the water channel aquaporin 4 (Aqp4) and the inward-directed potassium channel Kir4.1 to astroglial endfeet (Bragg et al, 2006;Sievers et al, 1994a,b). These channels are redistributed after injury and may contribute to the glial reactivity, in particular, the astrocyte swelling (Iandiev et al, 2006;Nesic et al, 2006;Ulbricht et al, 2008). Taken together, these data raise the possibility that alterations in BMastrocyte signaling may play a crucial role in the reaction to brain injury.…”

Section: Introductionmentioning

confidence: 88%

Conditional deletion of β1‐integrin in astroglia causes partial reactive gliosis

Robel

Mori

Zoubaa

et al. 2009

Glia

105

100

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Astrocytes play many pivotal roles in the adult brain, including their reaction to injury. A hallmark of astrocytes is the contact of their endfeet with the basement membrane surrounding blood vessels, but still relatively little is known about the signaling mediated at the contact site. Here, we examine the role of beta1-integrin at this interface by its conditional deletion using different Cre lines. Thereby, the protein was reduced only at postnatal stages either in both glia and neurons or specifically only in neurons. Strikingly, only the former resulted in reactive gliosis, with the hallmarks of reactive astrocytes comprising astrocyte hypertrophy and up-regulation of the intermediate filaments GFAP and vimentin as well as pericellular components, such as Tenascin-C and the DSD-1 proteoglycan. In addition, we also observed to a certain degree a non-cell autonomous activation of microglial cells after conditional beta1-integrin deletion. However, these reactive astrocytes did not divide, suggesting that the loss of beta1-integrin-mediated signaling is not sufficient to elicit proliferation of these cells as observed after brain injury. Interestingly, this partial reactive gliosis appeared in the absence of cell death and blood brain barrier disturbances. As these effects did not appear after neuron-specific deletion of beta1-integrin, we conclude that beta1-integrin-mediated signaling in astrocytes is required to promote their acquisition of a mature, nonreactive state. Alterations in beta1-integrin-mediated signaling may hence be implicated in eliciting specific aspects of reactive gliosis after injury.

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“…Such alterations have been observed in animal models of various retinal diseases, including ischemia-reperfusion, inflammation, diabetic retinopathy, blue-light injury, detachment, vein occlusion and proliferative vitreoretinopathy, as well as in Müller cells from patients with proliferative retinopathies (fig. 5a) [17,18,19,20,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,199]. Ischemia causes a decrease in Kir4.1 (but not Kir2.1) expression (fig.…”

Section: Dysfunctional Retinal Potassium Homeostasismentioning

confidence: 99%

“…Downregulation of carbonic anhydrase [14,15] and inwardly rectifying potassium (Kir) channels (fig. 1d, 2, 3a, b, d) [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] results in disturbances of retinal acid-base, ion and water homeostasis (see below) [7,39]. …”

Section: Müller Cell Gliosismentioning

confidence: 99%

Müller Glial Cells in Retinal Disease

Bringmann¹,

Wiedemann²

2011

Ophthalmologica

Self Cite

346

274

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Virtually all pathogenic stimuli activate Müller cells. Reactive Müller cells exert protective and toxic effects on photoreceptors and neurons. They contribute to oxidative stress and glutamate toxicity due to malfunctions of glutamate uptake and glutathione synthesis. Downregulation of potassium conductance disrupts transcellular potassium and water transport, resulting in neuronal hyperexcitability and edema. Protective effects of reactive Müller cells include upregulation of adenosine 5′-triphosphate (ATP)-degrading ectoenzymes, which enhances the extracellular availability of the neuroprotectant adenosine, abrogation of the osmotic release of ATP, which might protect retinal ganglion cells from apoptosis, and the release of antioxidants and neurotrophic factors. The dedifferentiation of reactive Müller cells to progenitor-like cells might have an impact on future therapeutic approaches. A better understanding of the gliotic mechanisms will be helpful in developing efficient therapeutic strategies aiming at increased protective and regenerative properties and decreased toxicity of reactive Müller cells.

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Proliferative gliosis causes mislocation and inactivation of inwardly rectifying K+ (Kir) channels in rabbit retinal glial cells

Cited by 25 publications

References 32 publications

Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS

Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS

Conditional deletion of β1‐integrin in astroglia causes partial reactive gliosis

Müller Glial Cells in Retinal Disease

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