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Connections Between Connexins, Calcium, and Cataracts in the Lens
There is a good deal of evidence that the lens generates an internal micro circulatory system, which brings metabolites, like glucose, and antioxidants, like ascorbate, into the lens along the extracellular spaces between cells. Calcium also ought to be carried into the lens by this system. If so, t...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2004
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233908/ https://www.ncbi.nlm.nih.gov/pubmed/15452195 http://dx.doi.org/10.1085/jgp.200409121 |
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author | Gao, Junyuan Sun, Xiurong Martinez-Wittinghan, Francisco J. Gong, Xiaohua White, Thomas W. Mathias, Richard T. |
author_facet | Gao, Junyuan Sun, Xiurong Martinez-Wittinghan, Francisco J. Gong, Xiaohua White, Thomas W. Mathias, Richard T. |
author_sort | Gao, Junyuan |
collection | PubMed |
description | There is a good deal of evidence that the lens generates an internal micro circulatory system, which brings metabolites, like glucose, and antioxidants, like ascorbate, into the lens along the extracellular spaces between cells. Calcium also ought to be carried into the lens by this system. If so, the only path for Ca(2+) to get out of the lens is to move down its electrochemical gradient into fiber cells, and then move by electrodiffusion from cell to cell through gap junctions to surface cells, where Ca-ATPase activity and Na/Ca exchange can transport it back into the aqueous or vitreous humors. The purpose of the present study was to test this calcium circulation hypothesis by studying calcium homeostasis in connexin (Cx46) knockout and (Cx46 for Cx50) knockin mouse lenses, which have different degrees of gap junction coupling. To measure intracellular calcium, FURA2 was injected into fiber cells, and the gradient in calcium concentration from center to surface was mapped in each type of lens. In wild-type lenses the coupling conductance of the mature fibers was ∼0.5 S/cm(2) of cell to cell contact, and the best fit to the calcium concentration data varied from 700 nM in the center to 300 nM at the surface. In the knockin lenses, the coupling conductance was ∼1.0 S/cm(2) and calcium varied from ∼500 nM at the center to 300 nM at the surface. Thus, when the coupling conductance doubled, the concentration gradient halved, as predicted by the model. In knockout lenses, the coupling conductance was zero, hence the efflux path was knocked out and calcium accumulated to ∼2 μM in central fibers. Knockout lenses also had a dense central cataract that extended from the center to about half the radius. Others have previously shown that this cataract involves activation of a calcium-dependent protease, Lp82. We can now expand on this finding to provide a hypothesis on each step that leads to cataract formation: knockout of Cx46 causes loss of coupling of mature fiber cells; the efflux path for calcium is therefore blocked; calcium accumulates in the central cells; at concentrations above ∼1 μM (from the center to about half way out of a 3-wk-old lens) Lp82 is activated; Lp82 cleaves cytoplasmic proteins (crystallins) in central cells; and the cleaved proteins aggregate and scatter light. |
format | Text |
id | pubmed-2233908 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2004 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22339082008-03-21 Connections Between Connexins, Calcium, and Cataracts in the Lens Gao, Junyuan Sun, Xiurong Martinez-Wittinghan, Francisco J. Gong, Xiaohua White, Thomas W. Mathias, Richard T. J Gen Physiol Article There is a good deal of evidence that the lens generates an internal micro circulatory system, which brings metabolites, like glucose, and antioxidants, like ascorbate, into the lens along the extracellular spaces between cells. Calcium also ought to be carried into the lens by this system. If so, the only path for Ca(2+) to get out of the lens is to move down its electrochemical gradient into fiber cells, and then move by electrodiffusion from cell to cell through gap junctions to surface cells, where Ca-ATPase activity and Na/Ca exchange can transport it back into the aqueous or vitreous humors. The purpose of the present study was to test this calcium circulation hypothesis by studying calcium homeostasis in connexin (Cx46) knockout and (Cx46 for Cx50) knockin mouse lenses, which have different degrees of gap junction coupling. To measure intracellular calcium, FURA2 was injected into fiber cells, and the gradient in calcium concentration from center to surface was mapped in each type of lens. In wild-type lenses the coupling conductance of the mature fibers was ∼0.5 S/cm(2) of cell to cell contact, and the best fit to the calcium concentration data varied from 700 nM in the center to 300 nM at the surface. In the knockin lenses, the coupling conductance was ∼1.0 S/cm(2) and calcium varied from ∼500 nM at the center to 300 nM at the surface. Thus, when the coupling conductance doubled, the concentration gradient halved, as predicted by the model. In knockout lenses, the coupling conductance was zero, hence the efflux path was knocked out and calcium accumulated to ∼2 μM in central fibers. Knockout lenses also had a dense central cataract that extended from the center to about half the radius. Others have previously shown that this cataract involves activation of a calcium-dependent protease, Lp82. We can now expand on this finding to provide a hypothesis on each step that leads to cataract formation: knockout of Cx46 causes loss of coupling of mature fiber cells; the efflux path for calcium is therefore blocked; calcium accumulates in the central cells; at concentrations above ∼1 μM (from the center to about half way out of a 3-wk-old lens) Lp82 is activated; Lp82 cleaves cytoplasmic proteins (crystallins) in central cells; and the cleaved proteins aggregate and scatter light. The Rockefeller University Press 2004-10 /pmc/articles/PMC2233908/ /pubmed/15452195 http://dx.doi.org/10.1085/jgp.200409121 Text en Copyright © 2004, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Gao, Junyuan Sun, Xiurong Martinez-Wittinghan, Francisco J. Gong, Xiaohua White, Thomas W. Mathias, Richard T. Connections Between Connexins, Calcium, and Cataracts in the Lens |
title | Connections Between Connexins, Calcium, and Cataracts in the Lens |
title_full | Connections Between Connexins, Calcium, and Cataracts in the Lens |
title_fullStr | Connections Between Connexins, Calcium, and Cataracts in the Lens |
title_full_unstemmed | Connections Between Connexins, Calcium, and Cataracts in the Lens |
title_short | Connections Between Connexins, Calcium, and Cataracts in the Lens |
title_sort | connections between connexins, calcium, and cataracts in the lens |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233908/ https://www.ncbi.nlm.nih.gov/pubmed/15452195 http://dx.doi.org/10.1085/jgp.200409121 |
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