Browsing by Author "Orellana Roca, Juan Andrés"

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    Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanol-induced Neuroinflammation in Rats
    (2019) Flores Bastias, Osvaldo; Gomez, Gonzalo I.; Orellana Roca, Juan Andrés; Karahanian, Eduardo
    Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury.
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    Activation of Pannexin-1 channels causes cell dysfunction and damage in mesangial cells derived from angiotensin II-exposed mice
    (Frontiers Media SA, 2024) Lucero, Claudia M.; Navarro, Laura; Barros-Osorio, Cristián; Cáceres-Conejeros, Patricio; Orellana Roca, Juan Andrés; Gómez, Gonzalo I.
    Copyright © 2024 Lucero, Navarro, Barros-Osorio, Cáceres-Conejeros, Orellana and Gómez.Chronic kidney disease (CKD) is a prevalent health concern associated with various pathological conditions, including hypertensive nephropathy. Mesangial cells are crucial in maintaining glomerular function, yet their involvement in CKD pathogenesis remains poorly understood. Recent evidence indicates that overactivation of Pannexin-1 (Panx1) channels could contribute to the pathogenesis and progression of various diseases. Although Panx1 is expressed in the kidney, its contribution to the dysfunction of renal cells during pathological conditions remains to be elucidated. This study aimed to investigate the impact of Panx1 channels on mesangial cell function in the context of hypertensive nephropathy. Using an Ang II-infused mouse model and primary mesangial cell cultures, we demonstrated that in vivo exposure to Ang II sensitizes cultured mesangial cells to show increased alterations when they are subjected to subsequent in vitro exposure to Ang II. Particularly, mesangial cell cultures treated with Ang II showed elevated activity of Panx1 channels and increased release of ATP. The latter was associated with enhanced basal intracellular Ca2+ ([Ca2+]i) and increased ATP-mediated [Ca2+]i responses. These effects were accompanied by increased lipid peroxidation and reduced cell viability. Crucially, all the adverse impacts evoked by Ang II were prevented by the blockade of Panx1 channels, underscoring their critical role in mediating cellular dysfunction in mesangial cells. By elucidating the mechanisms by which Ang II negatively impacts mesangial cell function, this study provides valuable insights into the pathogenesis of renal damage in hypertensive nephropathy.
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    Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes
    (2024) Gómez, Gonzalo I.; García-Rodríguez, Claudia; Marillán, Jesus E.; Vergara, Sergio A.; Alvear, Tanhia F.; Farias-Pasten, Arantza; Sáez, Juan C.; Retamal, Mauricio A.; Rovegno, Maximiliano; Ortiz, Fernando C.; Orellana Roca, Juan Andrés
    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 Ca2+ 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 Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ 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 [Ca2+](i) linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+](i). The [Ca2+](i)-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.
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    Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment
    (2018) Tapia-Rojas, Cheril; Carvajal Cachaña, Francisco Javier; Mira, Rodrigo G.; Arce, Camila; Manuel Lerma-Cabrera, Jose; Orellana Roca, Juan Andrés; Cerpa Nebott, Waldo Francisco; Quintanilla, Rodrigo A.
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    Amyloid beta-Induced Death in Neurons Involves Glial and Neuronal Hemichannels
    (2011) Orellana Roca, Juan Andrés; Shoji Sánchez, Kenji Fabricio; Sáez Pedraza, Pablo José; Sáez, Juan Carlos
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    Astrocytes inhibit nitric oxide-dependent Ca2+ dynamics in activated microglia: Involvement of ATP released via pannexin 1 channels
    (2013) Orellana Roca, Juan Andrés; Montero Ossandón, Trinidad; Bernhardi Montgomery, Rommy von
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    Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR-dependent transmission and short-term fear memory in the basolateral amygdala
    (2022) Linsambarth, Sergio; Carvajal Cachaña, Francisco Javier; Moraga Amaro, Rodrigo; Mendez, Luis; Tamburini, Giovanni; Jimenez, Ivanka; Antonio Verdugo, Daniel; Gomez, Gonzalo, I; Jury, Nur; Martinez, Pablo; van Zundert, Brigitte; Varela Nallar, Lorena; Retamal, Mauricio A.; Martin, Claire; Altenberg, Guillermo A.; Fiori, Mariana C.; Cerpa Nebott, Waldo Francisco; Orellana Roca, Juan Andrés; Stehberg, Jimmy
    Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se.
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    Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders
    (2021) Prieto Villalobos, Juan Carlos; Alvear Soto, Tanhia Francheska; Liberona, Andres; Lucero, Claudia M.; Martinez Araya, Claudio J.; Balmazabal, Javiera; Inostroza, Carla A.; Ramírez Rojas, Gigliola; Gomez, Gonzalo I.; Orellana Roca, Juan Andrés
    Maternal inflammation during pregnancy causes later-in-life alterations of the offspring's brain structure and function. These abnormalities increase the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder, microcephaly, and cerebral palsy. Here, we discuss how astrocytes might contribute to postnatal brain dysfunction following maternal inflammation, focusing on the signaling mediated by two families of plasma membrane channels: hemi-channels and pannexons. [Ca2+](i) imbalance linked to the opening of astrocytic hemichannels and pannexons could disturb essential functions that sustain astrocytic survival and astrocyte-to-neuron support, including energy and redox homeostasis, uptake of K+ and glutamate, and the delivery of neurotrophic factors and energy-rich metabolites. Both phenomena could make neurons more susceptible to the harmful effect of prenatal inflammation and the experience of a second immune challenge during adulthood. On the other hand, maternal inflammation could cause excitotoxicity by producing the release of high amounts of gliotransmitters via astrocytic hemichannels/pannexons, eliciting further neuronal damage. Understanding how hemichannels and pannexons participate in maternal inflammation-induced brain abnormalities could be critical for developing pharmacological therapies against neurological disorders observed in the offspring.
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    Cannabinoids Prevent the Amyloid beta-Induced Activation of Astroglial Hemichannels: A Neuroprotective Mechanism
    (2017) Gajardo Gómez, Rosario; Labra, Valeria C.; Maturana, Carola J.; Shoji Sánchez, Kenji Fabricio; Sáez, Juan Carlos; Orellana Roca, Juan Andrés
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    Cation permeation through connexin 43 hemichannels is cooperative, competitive and saturable with parameters depending on the permeant species
    (2011) Orellana Roca, Juan Andrés; Schalper Casanova, Kurt Alex.; Vargas Ríos, Aníbal Antonio; Sáez, Juan Carlos
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    Cell membrane permeabilization via connexin hemichannels in living and dying cells
    (2010) Sáez, Juan Carlos; Schalper Casanova, Kurt Alex; Orellana Roca, Juan Andrés; Shoji Sánchez, Kenji Fabricio
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    Connexin 43 Hemichannel Activity Promoted by Pro-Inflammatory Cytokines and High Glucose Alters Endothelial Cell Function
    (2018) Sáez, Juan Carlos; Contreras-Duarte, Susana; Gomez, Gonzalo I.; Labra, Valeria C.; Santibanez, Cristian A.; Gajardo Gómez, Rosario; Avendano, Beatriz C.; Diaz, Esteban F.; Montero, Trinidad D.; Velarde, Victoria; Orellana Roca, Juan Andrés
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    Connexin 43 hemichannels and pannexin-1 channels contribute to the alpha-synuclein-induced dysfunction and death of astrocytes
    (2019) Díaz Jara, Esteban Fernando; Labra Ramírez, Valeria Cristina; Alvear, Tanhia F.; Mellado, Luis A.; Inostroza, Carla A.; Oyarzún Isamitt, Juan Esteban; Salgado Cortés, Nicole Andrea; Quintanilla Gómez, Rodrigo Arthur; Orellana Roca, Juan Andrés
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    Connexin and pannexin hemichannels in inflammatory responses of glia and neurons
    (2012) Bennett, M.; Orellana Roca, Juan Andrés; Sáez, Juan Carlos
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    Connexin and Pannexin-Based Channels in Oligodendrocytes: Implications in Brain Health and Disease
    (2019) Vejar, Sebastián; Oyarzún Isamitt, Juan Esteban; Retamal, Mauricio A.; Ortiz, Fernando C.; Orellana Roca, Juan Andrés
    Oligodendrocytes are the myelin forming cells in the central nervous system (CNS). In addition to this main physiological function, these cells play key roles by providing energy substrates to neurons as well as information required to sustain proper synaptic transmission and plasticity at the CNS. The latter requires a fine coordinated intercellular communication with neurons and other glial cell types, including astrocytes. In mammals, tissue synchronization is mainly mediated by connexins and pannexins, two protein families that underpin the communication among neighboring cells through the formation of different plasma membrane channels. At one end, gap junction channels (GJCs; which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells allowing electrical and metabolic coupling. At the other end, hemichannels and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra-and extracellular compartments, serving as diffusion pathways of ions and small molecules. Here, we briefly review the current knowledge about the expression and function of hemichannels, pannexons and GJCs in oligodendrocytes, as well as the evidence regarding the possible role of these channels in metabolic and synaptic functions at the CNS. In particular, we focus on oligodendrocyte-astrocyte coupling during axon metabolic support and its implications in brain health and disease.
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    Connexins and pannexins : new insights into microglial functions and dysfunctions
    (2016) Gajardo Gómez, Rosario; Labra, V.; Orellana Roca, Juan Andrés
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    Currently used methods for identification and characterization of hemichannels
    (2008) Schalper Casanova, Kurt Alex; Palacios Prado, Nicolás ; Orellana Roca, Juan Andrés; Sáez, Juan Carlos
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    Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice
    (2013) Sáez Pedraza, Pablo José; Orellana Roca, Juan Andrés; Vega-Riveros, Natalia; Figueroa, Vania A.; Hernández Trejo, Diego Eduardo; Castro, Juan Francisco; Klein Posternack, Andrés David; Jean X. Jiang; Zanlungo Matsuhiro, Silvana; Sáez Carreño, Juan Carlos
    Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.