Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels

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dc.contributor.authorFernández Olivares, Ainoa
dc.contributor.authorDurán Jara, Eduardo
dc.contributor.authorVerdugo, Daniel A.
dc.contributor.authorFiori, Mariana C.
dc.contributor.authorAltenberg, Guillermo A.
dc.contributor.authorStehberg, Jimmy
dc.contributor.authorAlfaro, Iván
dc.contributor.authorCalderón, Juan Francisco
dc.contributor.authorRetamal, Mauricio A.
dc.date.accessioned2023-11-27T14:06:23Z
dc.date.available2023-11-27T14:06:23Z
dc.date.issued2022-07-01
dc.descriptionIndexación: Scopus.es
dc.description.abstractConnexin (Cxs) hemichannels participate in several physiological and pathological pro-cesses, but the molecular mechanisms that control their gating remain elusive. We aimed at deter-mining 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.es
dc.description.urihttps://www.mdpi.com/1422-0067/23/13/7252
dc.identifier.citationInternational Journal of Molecular Sciences, Volume 23, Issue 13, July-1 2022, Article number 7252es
dc.identifier.doi10.3390/ijms23137252
dc.identifier.issn1661-6596
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/54138
dc.language.isoenes
dc.publisherMDPIes
dc.rights.licenseCC BY 4.0 DEED Atribución 4.0 Internacional
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.subjectChannel permeabilityes
dc.subjectConnexinses
dc.subjectExtracellular loopses
dc.subjectPost-translational modificationes
dc.subjectRedox sensinges
dc.titleExtracellular Cysteines Are Critical to Form Functional Cx46 Hemichannelses
dc.typeArtículoes
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