Connexin hemichannel mediates glutathione transport and protects lens fiber cells against oxidative stress

Abstract

Elevated oxidized stress contributes to lens cataracts and gap junctions play important roles in maintaining lens transparency. Besides gap junctions, connexins form hemichannels. Here, we report a new mechanism of hemichannels that mediate transport of reductant glutathione into lens fiber cells and protect cells against oxidative stress. Hemichannels were opened in response to H2O2 in lens fiber cells and were inhibited by two dominant negative mutants of Cx50; Cx50P88S that inhibits both gap junctions and hemichannels and Cx50H156N that only inhibits hemichannels, but not gap junctions. Treatment with H2O2 increased the number of fiber cells under apoptosis and this increase was augmented with those two dominant negative mutants that disrupted both Cx46 and Cx50 hemichannels, while Cx50E48K that only impaired gap junctions did not have such effect. Moreover, hemichannels mediate uptake of glutathione and this uptake protected lens fiber cells against oxidative stress while impaired hemichannels blunted protective function of glutathione. Together, these results show that oxidative stress activates connexin hemichannels in the lens fiber cells and that hemichannels likely protect lens cell against oxidative damage through transporting extracellular reductants.