title: Connexin 46 (cx46) gap junctions provide a pathway for the delivery of glutathione to the lens nucleus.
abstract: Maintenance of adequate levels of glutathione (GSH) in the lens nucleus 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.
authors.affiliation: From the Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York 10036 and.
authors.forename: Nefeli
authors.initials: N
authors.lastname: Slavi
authors.affiliation: From the Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York 10036 and.
authors.forename: Clio
authors.initials: C
authors.lastname: Rubinos
authors.affiliation: the Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794.
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.affiliation: the Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794.
authors.forename: Caterina
authors.initials: C
authors.lastname: Sellitto
authors.affiliation: the Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
authors.affiliation: the Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794.
authors.forename: Richard
authors.initials: R
authors.lastname: Mathias
authors.affiliation: From the Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York 10036 and msrinivas@sunyopt.edu.
authors.forename: Miduturu
authors.initials: M
authors.lastname: Srinivas
mesh_terms: D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004058:Diffusion; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000378:metabolism* / Q000502:physiology; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism*; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D014981:Xenopus; D000099264:Connexin 50
chemical_list: D017630:Connexins; D005136:Eye Proteins; D005978:Glutathione; D019803:Glutathione Disulfide; D000099264:Connexin 50; C082917:GJA3 protein, human
keywords: Cataract; Connexin; Gap Junction; Lens; Oxidative Stress