Is the Gain of Hemichannel Activity a Common Feature Shared by Cx26 Syndromic Deafness Mutants?

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Gap junctions and hemichannels (HCs) are major pathways for intercellular signaling. Both are made of homologous proteins named connexins. Mutations in the gene encoding Cx26 account for a large proportion of genetic deafness. These can lead to non-syndromic and syndromic deafness. The syndromic phenotype also includes awful skin disease. Gain of hemichannel activity has been proposed as the pathogenic mechanism behind this syndrome. Here, to test this hypothesis we used HeLa cells transiently expressing the Cx26 non-syndromic (G12V) and the syndromic (G12R, N14Y and S17F), all located in the N-termini segment. Hemichannel activity was evaluated by measure the plasma membrane permeability to fluorescent tracers, YO-PRO (MW 375.5 charge +2) and ethidium (MW 314.4; charge +1) and single channels conductances by whole cell patch clamp. Bathed in a divalent free cations solution HeLa cells expressing the syndromic G12R mutant show four and five folds increase in the uptake of YOPRO and ethidium, respectively, when compared to cells expressing wild type Cx26 (WT Cx26). At the single channel level, the full open state of the G12R mutant was around 600 pS; almost twice of the WT Cx26. On the other hand, the non-syndromic G12V and syndromic N14Y and S17F (most severe clinical phenotype) behave like the WT Cx26. These findings suggest that most Cx26 syndromic mutants in the N-termini mediate their pathogenicity by other mechanism than gain in hemichannel activity. Supported by: Millenium Institute-CINV, FONDECYT 1090573 and Anillo ACT-1104 to ADM; IEG is supported by CONICYT.