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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
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Rodrigo Moraga-Amaro
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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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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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SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics
(2023)
Juan Prieto-Villalobos
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Claudia M. Lucero
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Maximiliano Rovegno
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Gonzalo I. Gómez
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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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Helicobacter pylori outer membrane vesicles induce astrocyte reactivity through nuclear factor-κappa B activation and cause neuronal damage in vivo in a murine model
(2023)
Esteban Palacios
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Lorena Lobos-González
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Simón Guerrero
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Marcelo J. Kogan
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Baohai Shao
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p><jats:italic>Helicobacter pylori (Hp)</jats:italic> infects the stomach of 50% of the world’s population. Importantly, chronic infection by this bacterium correlates with the appearance of several extra-gastric pathologies, including neurodegenerative diseases. In such conditions, brain astrocytes become reactive and neurotoxic. However, it is still unclear whether this highly prevalent bacterium or the nanosized outer membrane vesicles (OMVs) they produce, can reach the brain, thus affecting neurons/astrocytes. Here, we evaluated the effects of <jats:italic>Hp</jats:italic> OMVs on astrocytes and neurons in vivo and in vitro.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Purified OMVs were characterized by mass spectrometry (MS/MS). Labeled OMVs were administered orally or injected into the mouse tail vein to study OMV-brain distribution. By immunofluorescence of tissue samples, we evaluated: GFAP (astrocytes), βIII tubulin (neurons), and urease (OMVs). The in vitro effect of OMVs in astrocytes was assessed by monitoring NF-κB activation, expression of reactivity markers, cytokines in astrocyte-conditioned medium (ACM), and neuronal cell viability.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Urease and GroEL were prominent proteins in OMVs. Urease (OMVs) was present in the mouse brain and its detection coincided with astrocyte reactivity and neuronal damage. In vitro, OMVs induced astrocyte reactivity by increasing the intermediate filament proteins GFAP and vimentin, the plasma membrane α<jats:sub>V</jats:sub>β<jats:sub>3</jats:sub> integrin, and the hemichannel connexin 43. OMVs also produced neurotoxic factors and promoted the release of IFNγ in a manner dependent on the activation of the transcription factor NF-κB. Surface antigens on reactive astrocytes, as well as secreted factors in response to OMVs, were shown to inhibit neurite outgrowth and damage neurons.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>OMVs administered orally or injected into the mouse bloodstream reach the brain, altering astrocyte function and promoting neuronal damage in vivo. The effects of OMVs on astrocytes were confirmed in vitro and shown to be NF-κB-dependent. These findings suggest that <jats:italic>Hp</jats:italic> could trigger systemic effects by releasing nanosized vesicles that cross epithelial barriers and access the CNS, thus altering brain cells.</jats:p> </jats:sec>
Scopus© Citations 36 2
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Connexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein
(2023)
Isidora M. León-Fuentes
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María G. Salgado-Gil
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María S. Novoa
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RETAMAL LUCERO, MAURICIO ANTONIO
<jats:p>Cancer is a widespread and incurable disease caused by genetic mutations, leading to uncontrolled cell proliferation and metastasis. Connexins (Cx) are transmembrane proteins that facilitate intercellular communication via hemichannels and gap junction channels. Among them, Cx46 is found mostly in the eye lens. However, in pathological conditions, Cx46 has been observed in various types of cancers, such as glioblastoma, melanoma, and breast cancer. It has been demonstrated that elevated Cx46 levels in breast cancer contribute to cellular resistance to hypoxia, and it is an enhancer of cancer aggressiveness supporting a pro-tumoral role. Accordingly, Cx46 is associated with an increase in cancer stem cell phenotype. These cells display radio- and chemoresistance, high proliferative abilities, self-renewal, and differentiation capacities. This review aims to consolidate the knowledge of the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells.</jats:p>
Scopus© Citations 3 2
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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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GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels
(2022)
Ivanka Jiménez-Dinamarca
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Rachel Reyes-Lizana
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Yordan Lemunao-Inostroza
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Kevin Cárdenas
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Raimundo Castro-Lazo
<jats:p>Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.</jats:p>
17Scopus© Citations 9
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Hypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons
(2022)
Claudia M. Lucero
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Juan Prieto-Villalobos
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Lucas Marambio-Ruiz
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Javiera Balmazabal
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Tanhia F. Alvear
<jats:p>Hypertension is one of the most common risk factors for developing chronic cardiovascular diseases, including hypertensive nephropathy. Within the glomerulus, hypertension causes damage and activation of mesangial cells (MCs), eliciting the production of large amounts of vasoactive and proinflammatory agents. Accordingly, the activation of AT1 receptors by the vasoactive molecule angiotensin II (AngII) contributes to the pathogenesis of renal damage, which is mediated mostly by the dysfunction of intracellular Ca2+ ([Ca2+]i) signaling. Similarly, inflammation entails complex processes, where [Ca2+]i also play crucial roles. Deregulation of this second messenger increases cell damage and promotes fibrosis, reduces renal blood flow, and impairs the glomerular filtration barrier. In vertebrates, [Ca2+]i signaling depends, in part, on the activity of two families of large-pore channels: hemichannels and pannexons. Interestingly, the opening of these channels depends on [Ca2+]i signaling. In this review, we propose that the opening of channels formed by connexins and/or pannexins mediated by AngII induces the ATP release to the extracellular media, with the subsequent activation of purinergic receptors. This process could elicit Ca2+ overload and constitute a feed-forward mechanism, leading to kidney damage.</jats:p>
5Scopus© Citations 18
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Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens
(2022)
Mauricio A. Retamal
;
Guillermo A. Altenberg
<jats:p>Connexins are a family of proteins that can form two distinct types of channels: hemichannels and gap junction channels. Hemichannels are composed of six connexin subunits and when open allow for exchanges between the cytoplasm and the extracellular milieu. Gap junction channels are formed by head-to-head docking of two hemichannels in series, each one from one of two adjacent cells. These channels allow for exchanges between the cytoplasms of contacting cells. The lens is a transparent structure located in the eye that focuses light on the retina. The transparency of the lens depends on its lack of blood irrigation and the absence of organelles in its cells. To survive such complex metabolic scenario, lens cells express Cx43, Cx46 and Cx50, three connexins isoforms that form hemichannels and gap junction channels that allow for metabolic cooperation between lens cells. This review focuses on the roles of Cx46 hemichannels and gap junction channels in the lens under physiological conditions and in the formation of cataracts, with emphasis on the modulation by posttranslational modifications.</jats:p>
6Scopus© Citations 8
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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
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Francisco J. Carvajal
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Rodrigo Moraga‐Amaro
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Luis Mendez
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Giovanni Tamburini
Scopus© Citations 19 2

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