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Lens Gap Junctional Coupling Is Modulated by Connexin Identity and the Locus of Gene Expression

¹From the Department of Physiology and Biophysics, State University of New York, Stony Brook, New York; and the ²Departments of Neurobiology and ³Cell Biology, Harvard Medical School, Boston, Massachusetts.

PURPOSE. To investigate the effects of reducing connexin (Cx) diversity in the lens when the amount of connexin protein is nearly constant.

METHODS. Lenses in which the Cx50 coding region was replaced by that of Cx46 (knockin [KI]), were compared with wild type (WT) and Cx50-knockout (KO) lenses. Gap junctional conductance (G_j), and membrane conductance were evaluated by using frequency domain impedance of intact lenses.

RESULTS. KO of Cx50 produced small depolarized lenses with central opacities. KI of Cx46 did not restore growth, but rescued resting voltage and eliminated opacities. In WT lenses, the average G_j was approximately 1 S/cm² of cell-to-cell contact in the outer shell of differentiating fibers (DFs), whereas it was approximately half that value in the core of mature fibers (MFs). KO of Cx50 reduced G_j in DF to 44% of normal, whereas KI of Cx46 restored G_j to approximately 60% of normal. In addition, KI of Cx46 markedly increased G_j in MFs. In WT lenses, all gap junction channels in DFs close when pH is reduced, whereas those in MFs are insensitive to pH. KO of Cx50 made both DF and MF channels pH insensitive, whereas KI of Cx46 restored pH sensitivity of all DF channels without altering MF pH insensitivity

CONCLUSIONS. Lens size and fiber cell coupling conductance depended on which connexin was expressed on the Cx50 gene locus, whereas homeostasis of central fibers and normal gap junction gating were maintained when either connexin was expressed. The authors conclude that the roles of lens gap junction channels depend not only on the primary sequence of the expressed connexin, but also on the gene locus that expresses the connexin.

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