Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Slavi N
,
Rubinos C
,
Li L
,
Sellitto C
,
White TW
,
Mathias R
,
Srinivas M
.
???displayArticle.abstract???
Maintenance of adequate levels of glutathione (GSH) in the lensnucleus is critical for protection of lens proteins from the effects of oxidative stress and for lens transparency. How GSH is transported to the nucleus is unknown. We show that GSH diffuses to the nucleus from the outer cortex, where a high concentration of the anti-oxidant is established by synthesis or uptake, via the network of gap junctions. Using electrophysiological measurements, we found that channels formed by Cx46 and Cx50, the two connexin isoforms expressed in the lens, were moderately cation-selective (P(Na)/P(Cl) ∼5 for Cx46 and ∼3 for Cx50). Single channel permeation of the larger GSH anion was low but detectable (P(Na)/P(GSH) ∼12 for Cx46 and ∼8 for Cx50), whereas permeation of divalent anion glutathione disulfide (GSSG) was undetectable. Measurement of GSH levels in the lenses from connexin knock-out (KO) mice indicated Cx46, and not Cx50, is necessary for transport of GSH to the core. Levels of GSH in the nucleus were markedly reduced in Cx46 KO, whereas they were unaffected by Cx50 KO. We also show that GSH delivery to the nucleus is not dependent on the lens microcirculation, which is believed to be responsible for extracellular transport of other nutrients to membrane transporters in the core. These results indicate that glutathione diffuses from cortical fiber cells to the nucleus via gap junction channels formed by Cx46. We present a model of GSH diffusion from outer cells to inner fiber cells through gap junctions.
Baldo,
Spatial variations in membrane properties in the intact rat lens.
1992, Pubmed
Baldo,
Spatial variations in membrane properties in the intact rat lens.
1992,
Pubmed
Baldo,
Gap junctional coupling in lenses from alpha(8) connexin knockout mice.
2001,
Pubmed
Bova,
Major changes in human ocular UV protection with age.
2001,
Pubmed
Candia,
Fluid circulation determined in the isolated bovine lens.
2012,
Pubmed
Dickerson,
A new mixed disulfide species in human cataractous and aged lenses.
1993,
Pubmed
Donaldson,
Point: A critical appraisal of the lens circulation model--an experimental paradigm for understanding the maintenance of lens transparency?
2010,
Pubmed
Ganea,
Glutathione-related enzymes and the eye.
2006,
Pubmed
Gao,
Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling.
2011,
Pubmed
Gao,
The effects of age on lens transport.
2013,
Pubmed
Giblin,
Glutathione: a vital lens antioxidant.
2000,
Pubmed
Goldberg,
Selective transfer of endogenous metabolites through gap junctions composed of different connexins.
1999,
Pubmed
Gong,
Genetic factors influence cataract formation in alpha 3 connexin knockout mice.
1999,
Pubmed
Gong,
Gap junctional coupling in lenses lacking alpha3 connexin.
1998,
Pubmed
Gong,
Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice.
1997,
Pubmed
Harding,
Glutathione-protein mixed disulphides in human lens.
1969,
Pubmed
Harris,
Connexin channel permeability to cytoplasmic molecules.
2007,
Pubmed
Harris,
Emerging issues of connexin channels: biophysics fills the gap.
2001,
Pubmed
Kannan,
Identification of a novel, sodium-dependent, reduced glutathione transporter in the rat lens epithelium.
1996,
Pubmed
,
Xenbase
Kannan,
Molecular characterization of a reduced glutathione transporter in the lens.
1995,
Pubmed
,
Xenbase
Lim,
Mapping of glutathione and its precursor amino acids reveals a role for GLYT2 in glycine uptake in the lens core.
2007,
Pubmed
Lou,
Protein-thiol mixed disulfides in human lens.
1992,
Pubmed
Lou,
Redox regulation in the lens.
2003,
Pubmed
Maeda,
Structure of the connexin 26 gap junction channel at 3.5 A resolution.
2009,
Pubmed
Martinez-Wittinghan,
Dominant cataracts result from incongruous mixing of wild-type lens connexins.
2003,
Pubmed
Martinez-Wittinghan,
Lens gap junctional coupling is modulated by connexin identity and the locus of gene expression.
2004,
Pubmed
Mathias,
The lens circulation.
2007,
Pubmed
Mathias,
Physiological properties of the normal lens.
1997,
Pubmed
Paul,
Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane of Xenopus oocytes.
1991,
Pubmed
,
Xenbase
Rathbun,
Lenticular glutathione synthesis: rate-limiting factors in its regulation and decline.
1984,
Pubmed
Reddy,
Glutathione and its function in the lens--an overview.
1990,
Pubmed
Shestopalov,
Development of a macromolecular diffusion pathway in the lens.
2003,
Pubmed
Shi,
The stratified syncytium of the vertebrate lens.
2009,
Pubmed
Shi,
Further analysis of the lens phenotype in Lim2-deficient mice.
2011,
Pubmed
Srinivas,
Correlative studies of gating in Cx46 and Cx50 hemichannels and gap junction channels.
2005,
Pubmed
,
Xenbase
Srinivas,
Voltage dependence of macroscopic and unitary currents of gap junction channels formed by mouse connexin50 expressed in rat neuroblastoma cells.
1999,
Pubmed
Sweeney,
An impediment to glutathione diffusion in older normal human lenses: a possible precondition for nuclear cataract.
1998,
Pubmed
Sweeney,
Movement of cysteine in intact monkey lenses: the major site of entry is the germinative region.
2003,
Pubmed
Trexler,
The first extracellular loop domain is a major determinant of charge selectivity in connexin46 channels.
2000,
Pubmed
,
Xenbase
Truscott,
The state of sulphydryl groups in normal and cataractous human lenses.
1977,
Pubmed
Truscott,
Age-related nuclear cataract: a lens transport problem.
2000,
Pubmed
Wang,
Monovalent ion selectivity sequences of the rat connexin43 gap junction channel.
1997,
Pubmed
Wang,
Phosphorylation and truncation sites of bovine lens connexin 46 and connexin 50.
2009,
Pubmed
White,
Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts.
1998,
Pubmed
White,
Mouse Cx50, a functional member of the connexin family of gap junction proteins, is the lens fiber protein MP70.
1992,
Pubmed
,
Xenbase
