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Project Title
Carbon monoxide inhibits Cx46 HCs through a lipid peroxidation-dependent process which increases Cx46- Ca2+ sensitivity
Partner Organisations
Internal ID
1160227
Principal Investigator
Status
TERMINADO
Start Date
16 March 2016
End Date
20 March 2016

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Activation of Intra-nodose Ganglion P2X7 Receptors Elicit Increases in Neuronal Activity

2023 , Julio Alcayaga , Jorge Vera , Mauricio Reyna-Jeldes , Alejandra A. Covarrubias , Claudio Coddou , Esteban Díaz-Jara , Rodrigo Del Rio , RETAMAL LUCERO, MAURICIO ANTONIO

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Topical Application of Connexin43 Hemichannel Blocker Reduces Carotid Body-Mediated Chemoreflex Drive in Rats

2018 , David C. Andrade , Rodrigo Iturriaga , Camilo Toledo , Claudia M. Lucero , Hugo S. Díaz , Alexis Arce-Álvarez , RETAMAL LUCERO, MAURICIO ANTONIO , Noah J. Marcus , Julio Alcayaga , Rodrigo Del Rio

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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 , Jimmy Stehberg , Iván Alfaro , CALDERON GIADROSIC, JUAN FRANCISCO , Mauricio A. Retamal

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.

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Redox-mediated regulation of connexin proteins; focus on nitric oxide

2018 , Isaac E. García , Helmuth A. Sánchez , Agustín D. Martínez , RETAMAL LUCERO, MAURICIO ANTONIO

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Connexin43 Hemichannels in Satellite Glial Cells, Can They Influence Sensory Neuron Activity?

2017 , RETAMAL LUCERO, MAURICIO ANTONIO , Manuel A. Riquelme , Jimmy Stehberg , Julio Alcayaga

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Connexin-46 Contained in Extracellular Vesicles Enhance Malignancy Features in Breast Cancer Cells

2020 , ACUÑA ASTUDILLO, RODRIGO ANTONIO , Manuel Varas-Godoy , Viviana M. Berthoud , Ivan E. Alfaro , RETAMAL LUCERO, MAURICIO ANTONIO

Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six subunits of transmembrane proteins called connexins (Cx). For many years, it was believed that the loss of GJC-mediated intercellular communication was a hallmark in cancer development. However, nowadays this paradigm is changing. The connexin 46 (Cx46), which is almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and is correlated with tumor growth in a Xenograft mouse model. On the other hand, extracellular vesicles (EVs) have an important role in long-distance communication under physiological conditions. In the last decade, EVs also have been recognized as key players in cancer aggressiveness. The aim of this work was to explore the involvement of Cx46 in EV-mediated intercellular communication. Here, we demonstrated for the first time, that Cx46 is contained in EVs released from breast cancer cells overexpressing Cx46 (EVs-Cx46). This EV-Cx46 facilitates the interaction between EVs and the recipient cell resulting in an increase in their migration and invasion properties. Our results suggest that EV-Cx46 could be a marker of cancer malignancy and open the possibility to consider Cx46 as a new therapeutic target in cancer treatment.

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Contribution of connexin hemichannels to the decreases in cell viability induced by linoleic acid in the human lens epithelial cells (HLE-B3)

2020 , Vania A. Figueroa , Oscar Jara , Carolina A. Oliva , EZQUER, EDUARDO MARCELO , EZQUER, EDUARDO FERNANDO , RETAMAL LUCERO, MAURICIO ANTONIO , Agustín D. Martínez , Guillermo A. Altenberg , Aníbal A. Vargas

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4-Hydroxynonenal induces Cx46 hemichannel inhibition through its carbonylation

2020 , Mauricio A. Retamal , Mariana C. Fiori , Ainoa Fernandez-Olivares , Sergio Linsambarth , Francisca Peña , Daisy Quintana , Jimmy Stehberg , Guillermo A. Altenberg

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Connexin46 Expression Enhances Cancer Stem Cell and Epithelial-to-Mesenchymal Transition Characteristics of Human Breast Cancer MCF-7 Cells

2021 , ACUÑA ASTUDILLO, RODRIGO ANTONIO , Manuel Varas-Godoy , Diego Herrera-Sepulveda , Mauricio A. Retamal

Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered a strong tumor suppressor, but it is now recognized that some type of Cxs can be pro-tumorigenic. For example, Cx46 expression is increased in human breast cancer samples and correlates with cancer stem cell (CSC) characteristics in human glioma. Thus, we explored whether Cx46 and glioma cells, can set up CSC and epithelial-to-mesenchymal transition (EMT) properties in a breast cancer cell line. To this end, we transfected MCF-7 cells with Cx46 attached to a green fluorescent protein (Cx46GFP), and we determined how its expression orchestrates both the gene-expression and functional changes associated with CSC and EMT. We observed that Cx46GFP increased Sox2, Nanog, and OCT4 mRNA levels associated with a high capacity to form monoclonal colonies and tumorspheres. Similarly, Cx46GFP increased the mRNA levels of n-cadherin, Vimentin, Snail and Zeb1 to a higher migratory and invasive capacity. Furthermore, Cx46GFP transfected in MCF-7 cells induced the release of higher amounts of VEGF, which promoted angiogenesis in HUVEC cells. We demonstrated for the first time that Cx46 modulates CSC and EMT properties in breast cancer cells and thus could be relevant in the design of future cancer therapies.

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Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR‐dependent transmission and short‐term fear memory in the basolateral amygdala

2022 , Sergio Linsambarth , Francisco J. Carvajal , Rodrigo Moraga‐Amaro , Luis Mendez , Giovanni Tamburini , Ivanka Jimenez , Daniel Antonio Verdugo , Gonzalo I. Gómez , Nur Jury , Pablo Martínez , Brigitte Zundert , Lorena Varela‐Nallar , Mauricio A. Retamal , Claire Martin , Guillermo A. Altenberg , Mariana C. Fiori , Waldo Cerpa , Juan A. Orellana , Jimmy Stehberg

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