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    Lack of canonical activities of connexins in highly aggressive human prostate cancer cells
    (Springer Science and Business Media LLC, 2024-12-19)
    Catalina Asencio
    ;
    Loreto Véliz
    ;
    Emilia Flores-Faúndez
    ;
    Lorena Azócar
    ;
    Carolina E. Echeverría
    <jats:title>Abstract</jats:title><jats:p>Connexins (Cxs) have the ability to form channels that allow the exchange of ions/metabolites between adjacent cells (gap junction channels, GJC) or between the intra- and extra-cellular compartments (hemichannels, HC). Cxs were initially classified as tumor suppressors. However, more recently, it has been shown that Cxs exert anti- and pro-tumorigenic effects depending on the cell and tissue context. In prostate cancer (PCa), the expression and functionality of Cxs remain highly controversial. Here, we analyzed the expression pattern of Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 in PCa cell lines with increasing levels of tumor aggressiveness (LNCaP &lt; LNCaP-C4-2 &lt; Du-145 &lt; PC-3). In addition, GJ and HC activities were evaluated in the PCa cell lines using dye coupling and dye uptake assays, respectively. Lastly, the cellular localization of Cx26, Cx32, and Cx43 was analyzed in LNCaP and PC-3 cell lines using immunofluorescence analyses. Our results showed a positive association between the mRNA levels of Cx26, Cx37 and Cx45 and the degree of aggressiveness of PCa cells, a negative association in the case of Cx32 and Cx43, and no clear pattern for Cx40. At the protein level, a negative relationship between the expression of Cx26, Cx32 and Cx43 and the degree of aggressiveness of PCa cell lines was observed. No significant differences were observed for the expression of Cx37, Cx40, and Cx45 in PCa cell lines. At the functional level, only LNCaP cells showed moderate GJ activity and LNCaP and LNCaP-C4-2 cells showed HC activity. Immunofluorescence analyses confirmed that the majority of Cx26, Cx32, and Cx43 expression was localized in the cytoplasm of both LNCaP and PC3 cell lines. This data indicated that GJ and HC activities were moderately detected only in the less aggressive PCa cells, which suggest that Cxs expression in highly aggressive PCa cells could be associated to channel-independent roles.</jats:p>
    Scopus© Citations 3  1
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    Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes
    (2024)
    Gonzalo I. Gómez
    ;
    Claudia García-Rodríguez
    ;
    Jesús E. Marillán
    ;
    Sergio A. Vergara
    ;
    Tanhia F. Alvear
    <jats:p>Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca<jats:sup>2+</jats:sup> and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca<jats:sup>2+</jats:sup> overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca<jats:sup>2+</jats:sup> signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> linked to extracellular Ca<jats:sup>2+</jats:sup> influx and IP<jats:sub>3</jats:sub>-evoked Ca<jats:sup>2+</jats:sup> release from intracellular Ca<jats:sup>2+</jats:sup> stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>. The [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.</jats:p>
      11Scopus© Citations 4
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    Regulation of Intercellular Calcium Signaling Through Calcium Interactions with Connexin-Based Channels
    (2012)
    Juan A. Orellana
    ;
    Helmuth A. Sánchez
    ;
    Kurt A. Schalper
    ;
    Vania Figueroa
    ;
    Juan C. Sáez
    Scopus© Citations 38  1
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    Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: Gap junctions versus hemichannels
    (2013)
    Jegan Iyyathurai
    ;
    Catheleyne D'hondt
    ;
    Nan Wang
    ;
    Marijke De Bock
    ;
    Bernard Himpens
      5Scopus© Citations 86
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    SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics
    (2023)
    Juan Prieto-Villalobos
    ;
    Claudia M. Lucero
    ;
    Maximiliano Rovegno
    ;
    Gonzalo I. Gómez
    ;
    Mauricio A. Retamal  
    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19). An aspect of high uncertainty is whether the SARS-CoV-2 per se or the systemic inflammation induced by viral infection directly affects cellular function and survival in different tissues. It has been postulated that tissue dysfunction and damage observed in COVID-19 patients may rely on the direct effects of SARS-CoV-2 viral proteins. Previous evidence indicates that the human immunodeficiency virus and its envelope protein gp120 increase the activity of connexin 43 (Cx43) hemichannels with negative repercussions for cellular function and survival. Here, we evaluated whether the spike protein S1 of SARS-CoV-2 could impact the activity of Cx43 hemichannels.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We found that spike S1 time and dose-dependently increased the activity of Cx43 hemichannels in HeLa-Cx43 cells, as measured by dye uptake experiments. These responses were potentiated when the angiotensin-converting enzyme 2 (ACE2) was expressed in HeLa-Cx43 cells. Patch clamp experiments revealed that spike S1 increased unitary current events with conductances compatible with Cx43 hemichannels. In addition, Cx43 hemichannel opening evoked by spike S1 triggered the release of ATP and increased the [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> dynamics elicited by ATP.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We hypothesize that Cx43 hemichannels could represent potential pharmacological targets for developing therapies to counteract SARS-CoV-2 infection and their long-term consequences.</jats:p> </jats:sec>
      6Scopus© Citations 7
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    Over-activated hemichannels: A possible therapeutic target for human diseases
    (2021)
    Mauricio A. Retamal
    ;
    Ainoa Fernandez-Olivares
    ;
    Jimmy Stehberg
    Scopus© Citations 11  13
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      17  1Scopus© Citations 12
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    Interferon-γ and high glucose-induced opening of Cx43 hemichannels causes endothelial cell dysfunction and damage
    (2020)
    Juan C. Sáez
    ;
    Susana Contreras-Duarte
    ;
    Valeria C. Labra
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    Cristian A. Santibañez
    ;
    Luis A. Mellado
    Scopus© Citations 30  2
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    Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?
    (2020)
    María F. Rozas-Villanueva
    ;
    Paola Casanello
    ;
    MAURICIO ANTONIO RETAMAL LUCERO
    <jats:p>Preeclampsia is a pregnancy complication that appears after 20 weeks of gestation and is characterized by hypertension and proteinuria, affecting both mother and offspring. The cellular and molecular mechanisms that cause the development of preeclampsia are poorly understood. An important feature of preeclampsia is an increase in oxygen and nitrogen derived free radicals (reactive oxygen species/reactive nitrogen species (ROS/RNS), which seem to be central players setting the development and progression of preeclampsia. Cell-to-cell communication may be disrupted as well. Connexins (Cxs), a family of transmembrane proteins that form hemichannels and gap junction channels (GJCs), are essential in paracrine and autocrine cell communication, allowing the movement of signaling molecules between cells as well as between the cytoplasm and the extracellular media. GJCs and hemichannels are fundamental for communication between endothelial and smooth muscle cells and, therefore, in the control of vascular contraction and relaxation. In systemic vasculature, the activity of GJCs and hemichannels is modulated by ROS and RNS. Cxs participate in the development of the placenta and are expressed in placental vasculature. However, it is unknown whether Cxs are modulated by ROS/RNS in the placenta, or whether this potential modulation contributes to the pathogenesis of preeclampsia. Our review addresses the possible role of Cxs in preeclampsia, and the plausible modulation of Cxs-formed channels by ROS and RNS. We suggest these factors may contribute to the development of preeclampsia.</jats:p>
    Scopus© Citations 18  1
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