دورية أكاديمية
Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
| العنوان: | Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels |
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| المؤلفون: | Ainoa Fernández-Olivares, Eduardo Durán-Jara, Daniel A. Verdugo, Mariana C. Fiori, Guillermo A. Altenberg, Jimmy Stehberg, Iván Alfaro, Juan Francisco Calderón, Mauricio A. Retamal |
| المصدر: | International Journal of Molecular Sciences, Vol 23, Iss 13, p 7252 (2022) |
| بيانات النشر: | MDPI AG, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | redox sensing, connexins, extracellular loops, channel permeability, post-translational modification, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | Connexin (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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 1661-6596 |
| Relation: | https://www.mdpi.com/1422-0067/23/13/7252; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067 |
| DOI: | 10.3390/ijms23137252 |
| URL الوصول: | https://doaj.org/article/7e10c1102aed4344a991c3f109fa209d |
| رقم الأكسشن: | edsdoj.7e10c1102aed4344a991c3f109fa209d |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 16616596 |
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| DOI: | 10.3390/ijms23137252 |