Gap junctions and connexin hemichannels both contribute to the electrical properties of retinal pigment epithelium

Fadjukov, Julia; Wienbar, Sophia; Hakanen, Satu; Aho, Vesa; Vihinen‐Ranta, Maija; Ihalainen, Teemu O.; Schwartz, Gregory William; Nymark, Soile

doi:10.1085/jgp.202112916

Cited by 6 publications

(17 citation statements)

References 67 publications

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“…Adherens junctions are present as well, located just basally of and partially overlapping the tight junctions ( 74 ). The RPE cells are also connected and electrically coupled via gap junctions ( 75 ). The polarized distributions of various membrane transporters in RPE cells facilitate the healthy functioning of the retina and are involved in retinal fluid homeostasis.…”

Section: Mechanisms Of Macular Edemamentioning

confidence: 99%

Mechanisms of macular edema

et al. 2023

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Macular edema is the pathological accumulation of fluid in the central retina. It is a complication of many retinal diseases, including diabetic retinopathy, retinal vascular occlusions and uveitis, among others. Macular edema causes decreased visual acuity and, when chronic or refractory, can cause severe and permanent visual impairment and blindness. In most instances, it develops due to dysregulation of the blood-retinal barrier which permits infiltration of the retinal tissue by proteins and other solutes that are normally retained in the blood. The increase in osmotic pressure in the tissue drives fluid accumulation. Current treatments include vascular endothelial growth factor blockers, corticosteroids, and non-steroidal anti-inflammatory drugs. These treatments target vasoactive and inflammatory mediators that cause disruption to the blood-retinal barrier. In this review, a clinical overview of macular edema is provided, mechanisms of disease are discussed, highlighting processes targeted by current treatments, and areas of opportunity for future research are identified.

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Section: Mechanisms Of Macular Edemamentioning

confidence: 99%

Mechanisms of macular edema

et al. 2023

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“…Dissections of mouse RPE monolayers for patch clamp recording were performed under IR light in carbogenated AMES (A-1372-25; US Biological Life Sciences) media buffered with sodium bicarbonate as previously described (Fadjukov et al, 2022). Membrane voltage was recorded in whole-cell patch clamp configuration using current clamp mode (MultiClamp 700B; Molecular Devices).…”

Section: Patch Clamp Recordingsmentioning

confidence: 99%

“…Of the 21 connexin types found in the human genome, Cx43 is the most commonly expressed Cx isoform (Willecke et al, 2002). Cells of the retinal pigment epithelium (RPE) primarily express Cx43, but low levels of Cx36 have also been identified (Fadjukov et al, 2022;Malfait et al, 2001;Milićević et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

CDK5 activity in retinal pigment epithelium contributes to gap junction dynamics during phagocytosis

Fadjukov

Wienbar

Milićević

et al. 2023

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Retinal pigment epithelium (RPE) at the back of the eye is a monolayer of cells with an extensive network of gap junctions that contributes to retinal health in a multitude of ways. One of those roles is the phagocytosis of photoreceptor outer segments. This renewal is under circadian regulation and peaks after light onset. Connexin 43 (Cx43) is the most predominantly expressed gap junction protein in RPE. In this study, we examine how gap junctions and specifically, Cx43 phosphorylation, contribute to phagocytosis in both human embryonic stem cell derived RPE and mouse RPE monolayers. We show that both Rac1 and CDK5 have differences in protein localization at different points in phagocytosis, and that by using their effectors, the capability of RPE for phagocytosis changes. CDK5 has not yet been reported in RPE tissue, and here we show that it likely regulates Cx43 localization and resulting electrical coupling. We find that gap junctions in RPE are temporally highly dynamic during phagocytosis and that regulation of gap junctions via phosphorylation is likely critical for maintaining eye health.

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“…Some of these support functions—such as the secretion of growth factors and the renewal of photoreceptor membranes via phagocytosis of their outer segments—are regulated by voltage-gated ion channels ( 1 , 2 ), suggesting that the electrical properties of the RPE are important for retinal health and disease. In this issue of JGP , Fadjukov et al reveal that these electrical properties are regulated by both gap junctions and connexin hemichannels in the RPE ( 3 ).…”

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confidence: 99%

“…Electrical conductance through gap junctions is likely to lower a cell’s input resistance, thereby reducing its electrical excitability. Nymark and colleagues, including first author Julia Fadjukov, measured the input resistance of RPE cells in monolayer cultures derived from human embryonic stem cells and also in intact RPE isolated from mouse eyes ( 3 ). In both cases, treating cells with the gap junction blocking agent meclofenamic acid (MFA) dramatically increased input resistance, and this effect was reversed when the drug was washed out.…”

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confidence: 99%