Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Slavi, Nefeli; Rubiños, Clio; Li, Leping; Sellitto, Caterina; White, Thomas W.; Mathias, Richard T.; Srinivas, Miduturu

doi:10.1074/jbc.m114.597898

Cited by 48 publications

(56 citation statements)

References 41 publications

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“…These results indicate that Cx30 has unique long-lived properties at the cell surface. This property was previously thought to be restricted to lens gap junctions consisting of mammalian Cx46 (Jiang et al, 1993) or chick Cx56 (Berthoud et al, 1999) in enucleated fibre cells, where they maintain the metabolic homeostasis of the lens (Slavi et al, 2014). This leads to the question: why would Cx30 need to have an extended half-life at the cell surface when most other connexins are designed to turn over rapidly?…”

Section: Discussionmentioning

confidence: 99%

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

Kelly

Shao

Jagger

et al. 2015

Journal of Cell Science

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Section: Discussionmentioning

confidence: 99%

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

Kelly

Shao

Jagger

et al. 2015

Journal of Cell Science

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“…The decrease in GSH has been attributed to the development of a barrier to the diffusion of the antioxidant from the outer cortex to the fiber cells in the lens core. 20 Because GJ channels are permeable to GSH, 19 it is possible that the impediment to diffusion is due to an age-dependent decrease in GJ coupling in mature fiber cells in the aging human lens caused by accumulation of Cx46 subunits truncated at cytoplasmic loop and N-terminal domains. Spatially correlating the age-dependent accumulation of these truncations with decreases in coupling in cells interior to the barrier region with the glutathione redox state and calcium accumulation is a goal of our future studies.…”

Section: Discussionmentioning

confidence: 99%

“…11,16–18 Lens GJ channels are also permeable to antioxidant molecules, such as glutathione. 19 Therefore, they can contribute to the delivery of the antioxidant from outer fiber cells, 19,20 where a high concentration is established by synthesis or uptake, 21–24 to central fiber cells, which have minimal capacity for glutathione synthesis.…”

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confidence: 99%

Identification and Functional Assessment of Age-Dependent Truncations to Cx46 and Cx50 in the Human Lens

Slavi

Wang

Harvey

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeMany proteins in the lens undergo extensive posttranslational modifications (PTMs) with age, leading to alterations in their function. The extent to which lens gap junction proteins, Cx46 and Cx50, accumulate PTMs with aging is not known. In this study, we identified truncations in Cx46 and Cx50 in the human lens using mass spectrometry. We also examined the effect of truncations on channel function using electrophysiological measurements.MethodsHuman lenses were dissected into cortex, outer nucleus, and nucleus regions, and fiber cell membranes were subjected to trypsin digestion. Tryptic peptides were analyzed by liquid chromatography (LC)–electrospray tandem mass spectrometry (ESI/MS/MS). Effects of truncations on channel conductance, permeability, and gating were assessed in transfected cells.ResultsCleavage sites were identified in the C-terminus, the cytoplasmic loop, and the N-terminus of Cx46 and Cx50. Levels of C-terminal truncations, which were found at residues 238 to 251 in Cx46 and at residues 238 to 253 and 274 to 284 in Cx50, were similar in different lens regions. In contrast, levels of truncations in cytoplasmic loop and N-terminal domains of Cx46 and Cx50 increased dramatically from outer cortex to nucleus. Most of the C-terminally truncated proteins were functional, whereas truncations in the cytoplasmic loop did not result in the formation of functional channels.ConclusionsAccumulation of cytoplasmic loop and N-terminal truncations in the core might lead to decreases in coupling with age. This reduction is expected to lead to an increase in intracellular calcium and a decrease in levels of glutathione in the nucleus. These changes may ultimately lead to age-related nuclear cataracts.

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“…The role of oxidative stress and inflammation in cardiovascular disease and related conditions is well established and is affected by numerous intrinsic and extrinsic factors [38]. Several connexins were previously linked to redox homeostasis, including Cx40 [39], Cx43 [40] and Cx46 [41]. The mechanism of their involvement include intra- and extracellular exchange of small molecules that are critical for redox homeostasis, such as GSH [42], for which Cx50 was shown to be permeable [41].…”

Section: Discussionmentioning

confidence: 99%

“…Several connexins were previously linked to redox homeostasis, including Cx40 [39], Cx43 [40] and Cx46 [41]. The mechanism of their involvement include intra- and extracellular exchange of small molecules that are critical for redox homeostasis, such as GSH [42], for which Cx50 was shown to be permeable [41]. The heteromeric channels containing the mutant Cx50 could thus affect the redox homeostasis directly by modulating the flow of relevant ions, molecules or metabolites or through altered post-translational modifications and interactions with other cellular proteins [43].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

et al. 2016

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BackgroundSeveral members of connexin family of transmembrane proteins were previously implicated in distinct metabolic conditions. In this study we aimed to determine the effects of complete and heterozygous form of connexin50 gene (Gja8) mutation L7Q on metabolic profile and oxidative stress parameters in spontaneously hypertensive inbred rat strain (SHR).MethodsAdult, standard chow-fed male rats of SHR, heterozygous SHR-Dca+/− and SHR-Dca−/− coisogenic strains were used. At the age of 4 months, dexamethasone (2.6 μg/ml) was administered in the drinking water for three days. The lipidemic profile (cholesterol and triacylglycerol concentration in 20 lipoprotein fractions, chylomicron, VLDL, LDL and HDL particle sizes) together with 33 cytokines and hormones in serum and several oxidative stress parameters in plasma, liver, kidney and heart were assessed.ResultsSHR and SHR-Dca−/− rats had similar concentrations of triacylglycerols and cholesterol in all major lipoprotein fractions. The heterozygotes reached significantly highest levels of total (SHR-Dca+/−: 51.3 ± 7.2 vs. SHR: 34.5 ± 2.4 and SHR-Dca−/−: 34.4 ± 2.5 mg/dl, p = 0.026), chylomicron and VLDL triacylglycerols. The heterozygotes showed significantly lowest values of HDL cholesterol (40.9 ± 2.3 mg/dl) compared both to SHR (51.8 ± 2.2 mg/dl) and SHR-Dca−/− (48.6 ± 2.7 mg/dl). Total and LDL cholesterol in SHR-Dca+/− was lower compared to SHR. Glucose tolerance was improved and insulin concentrations were lowest in SHR-Dca−/− (1.11 ± 0.20 pg/ml) in comparison with both SHR (2.32 ± 0.49 pg/ml) and SHR-Dca+/− (3.04 ± 0.21 pg/ml). The heterozygous rats showed profile suggestive of increased oxidative stress as well as highest serum concentrations of several pro-inflammatory cytokines including interleukins 6, 12, 17, 18 and tumor necrosis factor alpha.ConclusionsOur results demonstrate that connexin50 mutation in heterozygous state affects significantly the lipid profile and the oxidative stress parameters in the spontaneously hypertensive rat strain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0376-3) contains supplementary material, which is available to authorized users.

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Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Cited by 48 publications

References 41 publications

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

Identification and Functional Assessment of Age-Dependent Truncations to Cx46 and Cx50 in the Human Lens

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

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