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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
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Loreto Véliz
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Emilia Flores-Faúndez
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Lorena Azócar
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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 < LNCaP-C4-2 < Du-145 < 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
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Claudia García-Rodríguez
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Jesús E. Marillán
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Sergio A. Vergara
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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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Remembrances of Dr. Michael V.L. Bennett by Iberoamerican Colleagues and Friends
(2024)
Verónica Abudara
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Ricardo C. Araneda
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Luis Barrio
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Viviana M. Berthoud
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Jorge E. Contreras
10
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Regulation of Intercellular Calcium Signaling Through Calcium Interactions with Connexin-Based Channels
(2012)
Juan A. Orellana
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Helmuth A. Sánchez
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Kurt A. Schalper
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Vania Figueroa
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Juan C. Sáez
Scopus© Citations 38 1
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Linoleic acid induces opening of connexin26 hemichannels through a PI3K/Akt/Ca2+-dependent pathway
(2013)
Vania Figueroa
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Pablo J. Sáez
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José D. Salas
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Daniela Salas
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Oscar Jara
Scopus© Citations 30 1
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Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala
(2012)
Jimmy Stehberg
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Rodrigo Moraga‐Amaro
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Christian Salazar
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Alvaro Becerra
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Cesar Echeverría
Scopus© Citations 201 1
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Modulation of gap junction channels and hemichannels by growth factors
(2012)
Kurt A. Schalper
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Manuel A. Riquelme
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María C. Brañes
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Agustín D. Martínez
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Jose Luis Arcos Alvarez
1Scopus© Citations 30
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ATP Is Required and Advances Cytokine-Induced Gap Junction Formation in Microglia In Vitro
(2013)
Pablo J. Sáez
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Kenji F. Shoji
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RETAMAL LUCERO, MAURICIO ANTONIO
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Paloma A. Harcha
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Gigliola Ramírez
<jats:p>Microglia are the immune cells in the central nervous system. After injury microglia release bioactive molecules, including cytokines and ATP, which modify the functional state of hemichannels (HCs) and gap junction channels (GJCs), affecting the intercellular communication via extracellular and intracellular compartments, respectively. Here, we studied the role of extracellular ATP and several cytokines as modulators of the functional state of microglial HCs and GJCs using dye uptake and dye coupling techniques, respectively. In microglia and the microglia cell line EOC20, ATP advanced the TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>/IFN-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math>-induced dye coupling, probably through the induction of IL-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math>release. Moreover, TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>/IFN-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math>, but not TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>plus ATP, increased dye uptake in EOC20 cells. Blockade of Cx43 and Panx1 HCs prevented dye coupling induced by TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>/IFN-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math>, but not TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>plus ATP. In addition, IL-6 prevented the induction of dye coupling and HC activity induced by TNF-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>/IFN-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math>in EOC20 cells. Our data support the notion that extracellular ATP affects the cellular communication between microglia through autocrine and paracrine mechanisms, which might affect the timing of immune response under neuroinflammatory conditions.</jats:p>
5Scopus© Citations 44
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Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine
(2023)
Luis A. Cea
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Walter Vásquez
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Romina Hernández-Salinas
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Alejandra Z. Vielma
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Mario Castillo-Ruiz
<jats:p>Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.</jats:p>
5Scopus© Citations 18
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Interferon-γ and high glucose-induced opening of Cx43 hemichannels causes endothelial cell dysfunction and damage
(2020)
Juan C. Sáez
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Susana Contreras-Duarte
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Valeria C. Labra
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Cristian A. Santibañez
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Luis A. Mellado
Scopus© Citations 30 2

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