Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels

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dc.contributor.authorFernández, Ainoa
dc.contributor.authorDurán, Eduardo
dc.contributor.authorVerdugo, Daniel
dc.contributor.authorFiori, Mariana
dc.contributor.authorAltenberg, Guillermo
dc.contributor.authorStehberg, Jimmy
dc.contributor.authorAlfaro, Iván
dc.contributor.authorCalderón, Juan
dc.contributor.authorRetamal, Mauricio
dc.date.accessioned2023-01-20T15:15:32Z
dc.date.available2023-01-20T15:15:32Z
dc.date.issued2022
dc.description.abstractConnexin (Cxs) hemichannels participate in several physiological and pathological processes, but the molecular mechanisms that control their gating remain elusive. We aimed at determining the role of extracellular cysteines (Cys) in the gating and function of Cx46 hemichannels. We studied Cx46 and mutated all of its extracellular Cys to alanine (Ala) (one at a time) and studied the effects of the Cys mutations on Cx46 expression, localization, and hemichannel activity. Wild-type Cx46 and Cys mutants were expressed at comparable levels, with similar cellular localization. However, functional experiments showed that hemichannels formed by the Cys mutants did not open either in response to membrane depolarization or removal of extracellular divalent cations. Molecular-dynamics simulations showed that Cys mutants may show a possible alteration in the electrostatic potential of the hemichannel pore and an altered disposition of important residues that could contribute to the selectivity and voltage dependency in the hemichannels. Replacement of extracellular Cys resulted in "permanently closed hemichannels", which is congruent with the inhibition of the Cx46 hemichannel by lipid peroxides, through the oxidation of extracellular Cys. These results point to the modification of extracellular Cys as potential targets for the treatment of Cx46-hemichannel associated pathologies, such as cataracts and cancer, and may shed light into the gating mechanisms of other Cx hemichannels.
dc.description.versionVersión publicada
dc.identifier.citationFernández-Olivares A, Durán-Jara E, Verdugo DA, Fiori MC, Altenberg GA, Stehberg J, Alfaro I, Calderón JF, Retamal MA. Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels. Int J Mol Sci. 2022 Jun 29;23(13):7252. doi: 10.3390/ijms23137252
dc.identifier.urihttps://doi.org/10.3390/ijms23137252
dc.identifier.urihttps://repositorio.udd.cl/handle/11447/6967
dc.language.isoen
dc.subjectConnexins
dc.subjectChannel permeability
dc.subjectExtracellular loops
dc.subjectPost-translational modification
dc.subjectRedox sensing
dc.titleExtracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
dc.typeArticle
dcterms.sourceInternational journal of molecular sciences

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