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Author: search.filters.author.Jimmy StehbergSubject: search.filters.subject.gap junction

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    Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
    (Springer Science and Business Media LLC, 2025-03-27)
    Ainoa Fernández-Olivares
    ;
    Viviana P Orellana
    ;
    Jesús Llanquinao
    ;
    NUÑEZ VASQUEZ, GONZALO ESTEBAN  
    ;
    Pablo Pérez-Moreno
    Scopus© Citations 1  10
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    The role of astrocytes in depression, its prevention, and treatment by targeting astroglial gliotransmitter release
    (2024)
    Yorley Duarte
    ;
    Daisy Quintana-Donoso
    ;
    Rodrigo Moraga-Amaro
    ;
    Ivanka Dinamarca
    ;
    Yordan Lemunao
    <jats:p>The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.</jats:p>
    Scopus© Citations 5  8
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    Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
    (2022)
    Ainoa Fernández-Olivares
    ;
    Eduardo Durán-Jara
    ;
    Daniel A. Verdugo
    ;
    Mariana C. Fiori
    ;
    Guillermo A. Altenberg
    <jats:p>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.</jats:p>
      2Scopus© Citations 6
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      17  1Scopus© Citations 12