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18 pages, 5836 KiB

Open AccessArticle

Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth

by Karthik Sathiyanadan, Florian Alonso, Sonia Domingos-Pereira, Tania Santoro, Lauriane Hamard, Valérie Cesson, Paolo Meda, Denise Nardelli-Haefliger and Jacques-Antoine Haefliger

Int. J. Mol. Sci. 2022, 23(6), 2930; https://doi.org/10.3390/ijms23062930 - 8 Mar 2022

Cited by 5 | Viewed by 2767

Abstract

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth [...] Read more.

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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13 pages, 2087 KiB

Open AccessArticle

Cx43 Promotes Endothelial Cell Migration and Angiogenesis via the Tyrosine Phosphatase SHP-2

by Hanna Mannell, Petra Kameritsch, Heike Beck, Alexander Pfeifer, Ulrich Pohl and Kristin Pogoda

Int. J. Mol. Sci. 2022, 23(1), 294; https://doi.org/10.3390/ijms23010294 - 28 Dec 2021

Cited by 15 | Viewed by 2605

Abstract

The gap junction protein connexin 43 (Cx43) is associated with increased cell migration and to related changes of the actin cytoskeleton, which is mediated via its C-terminal cytoplasmic tail and is independent of its channel function. Cx43 has been shown to possess an [...] Read more.

The gap junction protein connexin 43 (Cx43) is associated with increased cell migration and to related changes of the actin cytoskeleton, which is mediated via its C-terminal cytoplasmic tail and is independent of its channel function. Cx43 has been shown to possess an angiogenic potential, however, the role of Cx43 in endothelial cell migration has not yet been investigated. Here, we found that the knock-down of Cx43 by siRNA in human microvascular endothelial cells (HMEC) reduces migration, as assessed by a wound assay in vitro and impaired aortic vessel sprouting ex vivo. Immunoprecipitation of Cx43 revealed an interaction with the tyrosine phosphatase SHP-2, which enhanced its phosphatase activity, as observed in Cx43 expressing HeLa cells compared to cells treated with an empty vector. Interestingly, the expression of a dominant negative substrate trapping mutant SHP-2 (CS) in HMEC, via lentiviral transduction, also impaired endothelial migration to a similar extent as Cx43 siRNA compared to SHP-2 WT. Moreover, the reduction in endothelial migration upon Cx43 siRNA could not be rescued by the introduction of a constitutively active SHP-2 construct (EA). Our data demonstrate that Cx43 and SHP-2 mediate endothelial cell migration, revealing a novel interaction between Cx43 and SHP-2, which is essential for this process. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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17 pages, 4675 KiB

Open AccessArticle

Expression and Functionality of Connexin-Based Channels in Human Liver Cancer Cell Lines

by Kaat Leroy, Cícero Júlio Silva Costa, Alanah Pieters, Bruna dos Santos Rodrigues, Raf Van Campenhout, Axelle Cooreman, Andrés Tabernilla, Bruno Cogliati and Mathieu Vinken

Int. J. Mol. Sci. 2021, 22(22), 12187; https://doi.org/10.3390/ijms222212187 - 10 Nov 2021

Cited by 10 | Viewed by 3422

Abstract

Liver cancer cell lines are frequently used in vitro tools to test candidate anti-cancer agents as well as to elucidate mechanisms of liver carcinogenesis. Among such mechanisms is cellular communication mediated by connexin-based gap junctions. The present study investigated changes in connexin expression [...] Read more.

Liver cancer cell lines are frequently used in vitro tools to test candidate anti-cancer agents as well as to elucidate mechanisms of liver carcinogenesis. Among such mechanisms is cellular communication mediated by connexin-based gap junctions. The present study investigated changes in connexin expression and gap junction functionality in liver cancer in vitro. For this purpose, seven human liver cancer cell lines, as well as primary human hepatocytes, were subjected to connexin and gap junction analysis at the transcriptional, translational and activity level. Real-time quantitative reverse transcription polymerase chain reaction analysis showed enhanced expression of connexin43 in the majority of liver cancer cell lines at the expense of connexin32 and connexin26. Some of these changes were paralleled at the protein level, as evidenced by immunoblot analysis and in situ immunocytochemistry. Gap junctional intercellular communication, assessed by the scrape loading/dye transfer assay, was generally low in all liver cancer cell lines. Collectively, these results provide a full scenario of modifications in hepatocyte connexin production and gap junction activity in cultured liver cancer cell lines. The findings may be valuable for the selection of neoplastic hepatocytes for future mechanistic investigation and testing of anti-cancer drugs that target connexins and their channels. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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20 pages, 2561 KiB

Open AccessArticle

Panx1b Modulates the Luminance Response and Direction of Locomotion in the Zebrafish

by Nickie Safarian, Sarah Houshangi-Tabrizi, Christiane Zoidl and Georg R. Zoidl

Int. J. Mol. Sci. 2021, 22(21), 11750; https://doi.org/10.3390/ijms222111750 - 29 Oct 2021

Cited by 2 | Viewed by 3925

Abstract

Pannexin1 (Panx1) can form ATP-permeable channels that play roles in the physiology of the visual system. In the zebrafish two ohnologs of Panx1, Panx1a and Panx1b, have unique and shared channel properties and tissue expression patterns. Panx1a channels are located in horizontal cells [...] Read more.

Pannexin1 (Panx1) can form ATP-permeable channels that play roles in the physiology of the visual system. In the zebrafish two ohnologs of Panx1, Panx1a and Panx1b, have unique and shared channel properties and tissue expression patterns. Panx1a channels are located in horizontal cells of the outer retina and modulate light decrement detection through an ATP/pH-dependent mechanisms and adenosine/dopamine signaling. Here, we decipher how the strategic localization of Panx1b channels in the inner retina and ganglion cell layer modulates visually evoked motor behavior. We describe a panx1b knockout model generated by TALEN technology. The RNA-seq analysis of 6 days post-fertilization larvae is confirmed by real-time PCR and paired with testing of locomotion behaviors by visual motor and optomotor response tests. We show that the loss of Panx1b channels disrupts the retinal response to an abrupt loss of illumination and it decreases the larval ability to follow leftward direction of locomotion in low light conditions. We concluded that the loss of Panx1b channels compromises the final output of luminance as well as motion detection. The Panx1b protein also emerges as a modulator of the circadian clock system. The disruption of the circadian clock system in mutants suggests that Panx1b could participate in non-image forming processes in the inner retina. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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23 pages, 9190 KiB

Open AccessArticle

Connexin-Based Channel Activity Is Not Specifically Altered by Hepatocarcinogenic Chemicals

by Kaat Leroy, Alanah Pieters, Axelle Cooreman, Raf Van Campenhout, Bruno Cogliati and Mathieu Vinken

Int. J. Mol. Sci. 2021, 22(21), 11724; https://doi.org/10.3390/ijms222111724 - 29 Oct 2021

Cited by 3 | Viewed by 2303

Abstract

Connexin-based channels play key roles in cellular communication and can be affected by deleterious chemicals. In this study, the effects of various genotoxic carcinogenic compounds, non-genotoxic carcinogenic compounds and non-carcinogenic compounds on the expression and functionality of connexin-based channels, both gap junctions and [...] Read more.

Connexin-based channels play key roles in cellular communication and can be affected by deleterious chemicals. In this study, the effects of various genotoxic carcinogenic compounds, non-genotoxic carcinogenic compounds and non-carcinogenic compounds on the expression and functionality of connexin-based channels, both gap junctions and connexin hemichannels, were investigated in human hepatoma HepaRG cell cultures. Expression of connexin26, connexin32, and connexin43 was evaluated by means of real-time reverse transcription quantitative polymerase chain reaction analysis, immunoblot analysis and in situ immunostaining. Gap junction functionality was assessed via a scrape loading/dye transfer assay. Opening of connexin hemichannels was monitored by measuring extracellular release of adenosine triphosphate. It was found that both genotoxic and non-genotoxic carcinogenic compounds negatively affect connexin32 expression. However, no specific effects related to chemical type were observed at gap junction or connexin hemichannel functionality level. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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20 pages, 7204 KiB

Open AccessArticle

Connexin43 in Germ Cells Seems to Be Dispensable for Murine Spermatogenesis

by Kristina Rode, Marion Langeheine, Bettina Seeger and Ralph Brehm

Int. J. Mol. Sci. 2021, 22(15), 7924; https://doi.org/10.3390/ijms22157924 - 25 Jul 2021

Cited by 3 | Viewed by 3133

Abstract

Testicular Connexin43 (Cx43) connects adjacent Sertoli cells (SC) and SC to germ cells (GC) in the seminiferous epithelium and plays a crucial role in spermatogenesis. However, the distinction whether this results from impaired inter-SC communication or between GC and SC is not possible, [...] Read more.

Testicular Connexin43 (Cx43) connects adjacent Sertoli cells (SC) and SC to germ cells (GC) in the seminiferous epithelium and plays a crucial role in spermatogenesis. However, the distinction whether this results from impaired inter-SC communication or between GC and SC is not possible, so far. Thus, the question arises, whether a GC-specific Cx43 KO has similar effects on spermatogenesis as it is general or SC-specific KO. Using the Cre/loxP recombinase system, two conditional KO mouse lines lacking Cx43 in premeiotic (pGCCx43KO) or meiotic GC (mGCCx43KO) were generated. It was demonstrated by qRT-PCR that Cx43 mRNA was significantly decreased in adult pGCCx43KO mice, while it was also reduced in mGCCx43KO mice, yet not statistically significant. Body and testis weights, testicular histology, tubular diameter, numbers of intratubular cells and Cx43 protein synthesis and localization did not show any significant differences in semi-quantitative Western blot analysis and immunohistochemistry comparing adult male KO and WT mice of both mouse lines. Male KO mice were fertile. These results indicate that Cx43 in spermatogonia/spermatids does not seem to be essential for successful termination of spermatogenesis and fertility as it is known for Cx43 in somatic SC, but SC-GC communication might rather occur via heterotypic GJ channels. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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23 pages, 4969 KiB

Open AccessArticle

Differential Domain Distribution of gnomAD- and Disease-Linked Connexin Missense Variants

by Donglin Bai, Jiayi Wang, Tianhe Li, Ryan Chan, Mena Atalla, Robert C. Chen, Mohammad T. Khazaneh, Raphael J. An and Peter B. Stathopulos

Int. J. Mol. Sci. 2021, 22(15), 7832; https://doi.org/10.3390/ijms22157832 - 22 Jul 2021

Cited by 10 | Viewed by 2674

Abstract

Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. [...] Read more.

Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. With rapid advances in DNA sequencing technology, more variants are being identified not only in families and individuals with diseases but also in people in the general population without any apparent linkage to Mendelian inherited diseases. Nevertheless, it remains challenging to classify the pathogenicity of a newly identified connexin variant. Here, we analyzed the disease- and Genome Aggregation Database (gnomAD, as a proxy of the general population)-linked variants in the coding region of the four disease-linked α connexin genes. We found that the most abundant and position-sensitive missense variants showed distinct domain distribution preference between disease- and gnomAD-linked variants. Plotting missense variants on topological and structural models revealed that disease-linked missense variants are highly enriched on the structurally stable/resolved domains, especially the pore-lining domains, while the gnomAD-linked missense variants are highly enriched in the structurally unstable/unresolved domains, especially the carboxyl terminus. In addition, disease-linked variants tend to be on highly conserved residues and those positions show evolutionary co-variation, while the gnomAD-linked missense variants are likely on less conserved residue positions and on positions without co-variation. Collectively, the revealed distribution patterns of disease- and gnomAD-linked missense variants further our understanding of the GJ structure–biological function relationship, which is valuable for classifying the pathogenicity of newly identified connexin variants. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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13 pages, 13225 KiB

Open AccessArticle

Expression of Connexin43 Stimulates Endothelial Angiogenesis Independently of Gap Junctional Communication In Vitro

by Christoph Koepple, Zizi Zhou, Lena Huber, Matthias Schulte, Kjestine Schmidt, Torsten Gloe, Ulrich Kneser, Volker Jürgen Schmidt and Cor de Wit

Int. J. Mol. Sci. 2021, 22(14), 7400; https://doi.org/10.3390/ijms22147400 - 9 Jul 2021

Cited by 12 | Viewed by 2842

Abstract

Connexins (Cx) form gap junctions (GJ) and allow for intercellular communication. However, these proteins also modulate gene expression, growth, and cell migration. The downregulation of Cx43 impairs endothelial cell migration and angiogenetic potential. Conversely, endothelial Cx43 expression is upregulated in an in vivo [...] Read more.

Connexins (Cx) form gap junctions (GJ) and allow for intercellular communication. However, these proteins also modulate gene expression, growth, and cell migration. The downregulation of Cx43 impairs endothelial cell migration and angiogenetic potential. Conversely, endothelial Cx43 expression is upregulated in an in vivo angiogenesis model relying on hemodynamic forces. We studied the effects of Cx43 expression on tube formation and proliferation in HUVECs and examined its dependency on GJ communication. Expectedly, intercellular communication assessed by dye transfer was linked to Cx43 expression levels in HUVECs and was sensitive to a GJ blockade by the Cx43 mimetic peptide Gap27. The proliferation of HUVECs was not affected by Cx43 overexpression using Cx43 cDNA transfection, siRNA-mediated knockdown of Cx43, or the inhibition of GJ compared to the controls (transfection of an empty vector, scrambled siRNA, and the solvent). In contrast, endothelial tube and sprout formation in HUVECs was minimized after Cx43 knockdown and significantly enhanced after Cx43 overexpression. This was not affected by a GJ blockade (Gap27). We conclude that Cx43 expression positively modulates the angiogenic potential of endothelial cells independent of GJ communication. Since proliferation remained unaffected, we suggest that Cx43 protein may modulate endothelial cell migration, thereby supporting angiogenesis. The modulation of Cx43 expression may represent an exploitable principle for angiogenesis induction in clinical therapy. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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18 pages, 12434 KiB

Open AccessArticle

Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)⁺ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

by Paweł Kochanowski, Jessica Catapano, Maciej Pudełek, Tomasz Wróbel, Zbigniew Madeja, Damian Ryszawy and Jarosław Czyż

Int. J. Mol. Sci. 2021, 22(8), 4150; https://doi.org/10.3390/ijms22084150 - 16 Apr 2021

Cited by 16 | Viewed by 2972

Abstract

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic [...] Read more.

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMT^low (U87) and MGMT^high (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMT^high T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMT^low and MGMT^high cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMT^high T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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14 pages, 3311 KiB

Open AccessArticle

Gap Junctional Communication via Connexin43 between Purkinje Fibers and Working Myocytes Explains the Epicardial Activation Pattern in the Postnatal Mouse Left Ventricle

by Veronika Olejnickova, Matej Kocka, Alena Kvasilova, Hana Kolesova, Adam Dziacky, Tom Gidor, Lihi Gidor, Barbora Sankova, Martina Gregorovicova, Robert G. Gourdie and David Sedmera

Int. J. Mol. Sci. 2021, 22(5), 2475; https://doi.org/10.3390/ijms22052475 - 1 Mar 2021

Cited by 10 | Viewed by 3558

Abstract

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the [...] Read more.

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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18 pages, 15365 KiB

Open AccessArticle

Alteration of Cx37, Cx40, Cx43, Cx45, Panx1, and Renin Expression Patterns in Postnatal Kidneys of Dab1-/- (yotari) Mice

by Mirela Lozić, Natalija Filipović, Marija Jurić, Ivona Kosović, Benjamin Benzon, Ivana Šolić, Nela Kelam, Anita Racetin, Koichiro Watanabe, Yu Katsuyama, Masaki Ogata, Mirna Saraga-Babić and Katarina Vukojević

Int. J. Mol. Sci. 2021, 22(3), 1284; https://doi.org/10.3390/ijms22031284 - 28 Jan 2021

Cited by 15 | Viewed by 3824

Abstract

Numerous evidence corroborates roles of gap junctions/hemichannels in proper kidney development. We analyzed how Dab1 gene functional silencing influences expression and localization of Cx37, Cx40, Cx43, Cx45, Panx1 and renin in postnatal kidneys of yotari mice, by using immunohistochemistry and electron microscopy. Dab1 [...] Read more.

Numerous evidence corroborates roles of gap junctions/hemichannels in proper kidney development. We analyzed how Dab1 gene functional silencing influences expression and localization of Cx37, Cx40, Cx43, Cx45, Panx1 and renin in postnatal kidneys of yotari mice, by using immunohistochemistry and electron microscopy. Dab1 Δ102/221 might lead to the activation of c-Src tyrosine kinase, causing the upregulation of Cx43 in the medulla of yotari mice. The expression of renin was more prominent in yotari mice (p < 0.001). Renin granules were unusually present inside the vascular walls of glomeruli capillaries, in proximal and distal convoluted tubules and in the medulla. Disfunction of Cx40 is likely responsible for increased atypically positioned renin cells which release renin in an uncontrolled fashion, but this doesn’t rule out simultaneous involvement of other Cxs, such as Cx45 which was significantly increased in the yotari cortex. The decreased Cx37 expression in yotari medulla might contribute to hypertension reduction provoked by high renin expression. These findings imply the relevance of Cxs/Panx1 as markers of impaired kidney function (high renin) in yotari mice and that they have a role in the preservation of intercellular signaling and implicate connexopathies as the cause of premature death of yotari mice. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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12 pages, 2824 KiB

Open AccessArticle

Tonabersat Inhibits Connexin43 Hemichannel Opening and Inflammasome Activation in an In Vitro Retinal Epithelial Cell Model of Diabetic Retinopathy

by Heather Lyon, Avik Shome, Ilva D. Rupenthal, Colin R. Green and Odunayo O. Mugisho

Int. J. Mol. Sci. 2021, 22(1), 298; https://doi.org/10.3390/ijms22010298 - 30 Dec 2020

Cited by 30 | Viewed by 3354

Abstract

This study was undertaken to evaluate the connexin hemichannel blocker tonabersat for the inhibition of inflammasome activation and use as a potential treatment for diabetic retinopathy. Human retinal pigment epithelial cells (ARPE-19) were stimulated with hyperglycemia and the inflammatory cytokines IL-1β and TNFα [...] Read more.

This study was undertaken to evaluate the connexin hemichannel blocker tonabersat for the inhibition of inflammasome activation and use as a potential treatment for diabetic retinopathy. Human retinal pigment epithelial cells (ARPE-19) were stimulated with hyperglycemia and the inflammatory cytokines IL-1β and TNFα in order to mimic diabetic retinopathy molecular signs in vitro. Immunohistochemistry was used to evaluate the effect of tonabersat treatment on NLRP3, NLRP1, and cleaved caspase-1 expression and distribution. A Luminex cytokine release assay was performed to determine whether tonabersat affected proinflammatory cytokine release. NLRP1 was not activated in ARPE-19 cells, and IL-18 was not produced under disease conditions. However, NLRP3 and cleaved caspase-1 complex formation increased with hyperglycemia and cytokine challenge but was inhibited by tonabersat treatment. It also prevented the release of proinflammatory cytokines IL-1β, VEGF, and IL-6. Tonabersat therefore has the potential to reduce inflammasome-mediated inflammation in diabetic retinopathy. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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21 pages, 6187 KiB

Open AccessArticle

Expression of Connexins 37, 43 and 45 in Developing Human Spinal Cord and Ganglia

by Marija Jurić, Julia Zeitler, Katarina Vukojević, Ivana Bočina, Maximilian Grobe, Genia Kretzschmar, Mirna Saraga-Babić and Natalija Filipović

Int. J. Mol. Sci. 2020, 21(24), 9356; https://doi.org/10.3390/ijms21249356 - 8 Dec 2020

Cited by 8 | Viewed by 3104

Abstract

Direct intercellular communication via gap junctions has an important role in the development of the nervous system, ranging from cell migration and neuronal differentiation to the formation of neuronal activity patterns. This study characterized and compared the specific spatio-temporal expression patterns of connexins [...] Read more.

Direct intercellular communication via gap junctions has an important role in the development of the nervous system, ranging from cell migration and neuronal differentiation to the formation of neuronal activity patterns. This study characterized and compared the specific spatio-temporal expression patterns of connexins (Cxs) 37, 43 and 45 during early human developmental stages (since the 5th until the 10th developmental week) in the spinal cord (SC) and dorsal root ganglia (DRG) using double immunofluorescence and transmission electron microscopy. We found the expression of all three investigated Cxs during early human development in all the areas of interest, in the SC, DRG, developing paravertebral ganglia of the sympathetic trunk, notochord and all three meningeal layers, with predominant expression of Cx37. Comparing the expression of different Cxs between distinct developmental periods, we did not find significant differences. Specific spatio-temporal pattern of Cxs expression might reflect their relevance in the development of all areas of interest via cellular interconnectivity and synchronization during the late embryonic and early fetal period of human development. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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17 pages, 5075 KiB

Open AccessArticle

Connexin Signaling in the Juxtaglomerular Apparatus (JGA) of Developing, Postnatal Healthy and Nephrotic Human Kidneys

by Ivona Kosovic, Natalija Filipovic, Benjamin Benzon, Ivana Bocina, Merica Glavina Durdov, Katarina Vukojevic, Marijan Saraga and Mirna Saraga-Babic

Int. J. Mol. Sci. 2020, 21(21), 8349; https://doi.org/10.3390/ijms21218349 - 6 Nov 2020

Cited by 10 | Viewed by 3637

Abstract

Our study analyzed the expression pattern of different connexins (Cxs) and renin positive cells in the juxtaglomerular apparatus (JGA) of developing, postnatal healthy human kidneys and in nephrotic syndrome of the Finnish type (CNF), by using double immunofluorescence, electron microscopy and statistical measuring. [...] Read more.

Our study analyzed the expression pattern of different connexins (Cxs) and renin positive cells in the juxtaglomerular apparatus (JGA) of developing, postnatal healthy human kidneys and in nephrotic syndrome of the Finnish type (CNF), by using double immunofluorescence, electron microscopy and statistical measuring. The JGA contained several cell types connected by Cxs, and consisting of macula densa, extraglomerular mesangium (EM) and juxtaglomerular cells (JC), which release renin involved in renin-angiotensin- aldosteron system (RAS) of arterial blood pressure control. During JGA development, strong Cx40 expression gradually decreased, while expression of Cx37, Cx43 and Cx45 increased, postnatally showing more equalized expression patterning. In parallel, initially dispersed renin cells localized to JGA, and greatly increased expression in postnatal kidneys. In CNF kidneys, increased levels of Cx43, Cx37 and Cx45 co-localized with accumulations of renin cells in JGA. Additionally, they reappeared in extraglomerular mesangial cells, indicating association between return to embryonic Cxs patterning and pathologically changed kidney tissue. Based on the described Cxs and renin expression patterning, we suggest involvement of Cx40 primarily in the formation of JGA in developing kidneys, while Cx37, Cx43 and Cx45 might participate in JGA signal transfer important for postnatal maintenance of kidney function and blood pressure control. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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14 pages, 3064 KiB

Open AccessArticle

Pannexin-1 Deficiency Decreases Epileptic Activity in Mice

by Mark S. Aquilino, Paige Whyte-Fagundes, Mark K. Lukewich, Liang Zhang, Berj L. Bardakjian, Georg R. Zoidl and Peter L. Carlen

Int. J. Mol. Sci. 2020, 21(20), 7510; https://doi.org/10.3390/ijms21207510 - 12 Oct 2020

Cited by 19 | Viewed by 3663

Abstract

Objective: Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 [...] Read more.

Objective: Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models—(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion. Results: Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta–gamma and delta-HF rhythms in the Panx1 knockout. Significance: These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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18 pages, 5259 KiB

Open AccessArticle

Cholestasis Differentially Affects Liver Connexins

by Axelle Cooreman, Raf Van Campenhout, Sara Crespo Yanguas, Eva Gijbels, Kaat Leroy, Alanah Pieters, Andrés Tabernilla, Pieter Van Brantegem, Pieter Annaert, Bruno Cogliati and Mathieu Vinken

Int. J. Mol. Sci. 2020, 21(18), 6534; https://doi.org/10.3390/ijms21186534 - 7 Sep 2020

Cited by 11 | Viewed by 3746

Abstract

Connexins are goal keepers of tissue homeostasis, including in the liver. As a result, they are frequently involved in disease. The current study was set up to investigate the effects of cholestatic disease on the production of connexin26, connexin32 and connexin43 in the [...] Read more.

Connexins are goal keepers of tissue homeostasis, including in the liver. As a result, they are frequently involved in disease. The current study was set up to investigate the effects of cholestatic disease on the production of connexin26, connexin32 and connexin43 in the liver. For this purpose, bile duct ligation, a well-known trigger of cholestatic liver injury, was applied to mice. In parallel, human hepatoma HepaRG cell cultures were exposed to cholestatic drugs and bile acids. Samples from both the in vivo and in vitro settings were subsequently subjected to assessment of mRNA and protein quantities as well as to in situ immunostaining. While the outcome of cholestasis on connexin26 and connexin43 varied among experimental settings, a more generalized repressing effect was seen for connexin32. This has also been observed in many other liver pathologies and could suggest a role for connexin32 as a robust biomarker of liver disease and toxicity. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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21 pages, 2729 KiB

Open AccessArticle

Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

by Lucie Čtveráčková, Daniel Jančula, Jan Raška, Pavel Babica and Iva Sovadinová

Int. J. Mol. Sci. 2020, 21(17), 6069; https://doi.org/10.3390/ijms21176069 - 23 Aug 2020

Cited by 14 | Viewed by 3781

Abstract

Humans are exposed to phthalates released from plastics, cosmetics, or food on a daily basis. Phthalates have low acute liver toxicity, but their chronic exposures could induce molecular and cellular effects linked to adverse health outcomes, such as liver tumor promotion or chronic [...] Read more.

Humans are exposed to phthalates released from plastics, cosmetics, or food on a daily basis. Phthalates have low acute liver toxicity, but their chronic exposures could induce molecular and cellular effects linked to adverse health outcomes, such as liver tumor promotion or chronic liver diseases. The alternation of gap junctional intercellular communication (GJIC) and MAPK-Erk1/2 pathways in liver progenitor or oval cells can disrupt liver tissue homeostatic mechanisms and affect the development and severity of these adverse outcomes. Our study with 20 different phthalates revealed their structurally dependent effects on liver GJIC and MAPK-Erk1/2 signaling in rat liver WB-F344 cell line with characteristics of liver oval cells. The phthalates with a medium-length side chain (3–6 C) were the most potent dysregulators of GJIC and activators of MAPK-Erk1/2. The effects occurred rapidly, suggesting the activation of non-genomic (non-transcriptional) mechanisms directly by the parental compounds. Short-chain phthalates (1–2 C) did not dysregulate GJIC even after longer exposures and did not activate MAPK-Erk1/2. Longer chain (≥7 C) phthalates, such as DEHP or DINP, moderately activated MAPK-Erk1/2, but inhibited GJIC only after prolonged exposures (>12 h), suggesting that GJIC dysregulation occurs via genomic mechanisms, or (bio)transformation. Overall, medium-chain phthalates rapidly affected the key tissue homeostatic mechanisms in the liver oval cell population via non-genomic pathways, which might contribute to the development of chronic liver toxicity and diseases. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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16 pages, 2461 KiB

Open AccessArticle

Endocytosis of Connexin 36 is Mediated by Interaction with Caveolin-1

by Anna Kotova, Ksenia Timonina and Georg R. Zoidl

Int. J. Mol. Sci. 2020, 21(15), 5401; https://doi.org/10.3390/ijms21155401 - 29 Jul 2020

Cited by 11 | Viewed by 4198

Abstract

The gap junctional protein connexin 36 (Cx36) has been co-purified with the lipid raft protein caveolin-1 (Cav-1). The relevance of an interaction between the two proteins is unknown. In this study, we explored the significance of Cav-1 interaction in the context of intracellular [...] Read more.

The gap junctional protein connexin 36 (Cx36) has been co-purified with the lipid raft protein caveolin-1 (Cav-1). The relevance of an interaction between the two proteins is unknown. In this study, we explored the significance of Cav-1 interaction in the context of intracellular and membrane transport of Cx36. Coimmunoprecipitation assays and Förster resonance energy transfer analysis (FRET) were used to confirm the interaction between the two proteins in the Neuro 2a cell line. We found that the Cx36 and Cav-1 interaction was dependent on the intracellular calcium levels. By employing different microscopy techniques, we demonstrated that Cav-1 enhances the vesicular transport of Cx36. Pharmacological interventions coupled with cell surface biotinylation assays and FRET analysis revealed that Cav-1 regulates membrane localization of Cx36. Our data indicate that the interaction between Cx36 and Cav-1 plays a role in the internalization of Cx36 by a caveolin-dependent pathway. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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Review

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15 pages, 1644 KiB

Open AccessReview

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

by Jorge Enrique González-Casanova, Samuel Durán-Agüero, Nelson Javier Caro-Fuentes, Maria Elena Gamboa-Arancibia, Tamara Bruna, Valmore Bermúdez and Diana Marcela Rojas-Gómez

Int. J. Mol. Sci. 2021, 22(22), 12145; https://doi.org/10.3390/ijms222212145 - 10 Nov 2021

Cited by 8 | Viewed by 3316

Abstract

Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, [...] Read more.

Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, understanding the biological regulation of adipose tissue is of fundamental relevance. Connexin, a protein that forms intercellular membrane channels of gap junctions and unopposed hemichannels, plays a key role in adipogenesis and in the maintenance of adipose tissue homeostasis. The expression and function of Connexin 43 (Cx43) during the different stages of the adipogenesis are differentially regulated. Moreover, it has been shown that cell–cell communication decreases dramatically upon differentiation into adipocytes. Furthermore, inhibition of Cx43 degradation or constitutive overexpression of Cx43 blocks adipocyte differentiation. In the first events of adipogenesis, the connexin is highly phosphorylated, which is likely associated with enhanced Gap Junction (GJ) communication. In an intermediate state of adipocyte differentiation, Cx43 phosphorylation decreases, as it is displaced from the membrane and degraded through the proteasome; thus, Cx43 total protein is reduced. Cx is involved in cardiac disease as well as in obesity-related cardiovascular diseases. Different studies suggest that obesity together with a high-fat diet are related to the production of remodeling factors associated with expression and distribution of Cx43 in the atrium. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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23 pages, 1545 KiB

Open AccessReview

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

by Juan Prieto-Villalobos, Tanhia F. Alvear, Andrés Liberona, Claudia M. Lucero, Claudio J. Martínez-Araya, Javiera Balmazabal, Carla A. Inostroza, Gigliola Ramírez, Gonzalo I. Gómez and Juan A. Orellana

Int. J. Mol. Sci. 2021, 22(17), 9503; https://doi.org/10.3390/ijms22179503 - 1 Sep 2021

Cited by 15 | Viewed by 4655

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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17 pages, 1231 KiB

Open AccessReview

Receptor–Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors

by Diego Guidolin, Cinzia Tortorella, Manuela Marcoli, Chiara Cervetto, Guido Maura and Luigi F. Agnati

Int. J. Mol. Sci. 2021, 22(16), 8656; https://doi.org/10.3390/ijms22168656 - 12 Aug 2021

Cited by 9 | Viewed by 2789

Abstract

The discovery that receptors from all families can establish allosteric receptor–receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, [...] Read more.

The discovery that receptors from all families can establish allosteric receptor–receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, most research in the field has focused on neuronal populations and has led to the identification of many receptor complexes representing an important mechanism to fine-tune synaptic efficiency. Receptor–receptor interactions, however, also modulate glia–neuron and glia–glia intercellular communication, with significant consequences on synaptic activity and brain network plasticity. The research on this topic is probably still at the beginning and, here, available evidence will be reviewed and discussed. It may also be of potential interest from a pharmacological standpoint, opening the possibility to explore, inter alia, glia-based neuroprotective therapeutic strategies. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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23 pages, 5010 KiB

Open AccessReview

Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond

by Samantha Minh Thy Nguyen, Chase Preston Rupprecht, Aaisha Haque, Debendra Pattanaik, Joseph Yusin and Guha Krishnaswamy

Int. J. Mol. Sci. 2021, 22(15), 7785; https://doi.org/10.3390/ijms22157785 - 21 Jul 2021

Cited by 88 | Viewed by 16954

Abstract

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell [...] Read more.

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC₄, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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15 pages, 873 KiB

Open AccessReview

Pannexin-1 Channels as Mediators of Neuroinflammation

by Joon Ho Seo, Miloni S. Dalal and Jorge E. Contreras

Int. J. Mol. Sci. 2021, 22(10), 5189; https://doi.org/10.3390/ijms22105189 - 14 May 2021

Cited by 31 | Viewed by 5856

Abstract

Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which [...] Read more.

Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which alter the functionality of nearby tissues and might mediate the recruitment of leukocytes to the injury site. If this process persists or is exacerbated, it prevents the adequate resolution of the inflammation, and ultimately enhances secondary damage. Adenosine 5′ triphosphate (ATP) is among the molecules released that trigger an inflammatory response, and it serves as a chemotactic and endogenous danger signal. Extracellular ATP activates multiple purinergic receptors (P2X and P2Y) that have been shown to promote neuroinflammation in a variety of CNS diseases. Recent studies have shown that Pannexin-1 (Panx1) channels are the principal conduits of ATP release from dying cells and innate immune cells in the brain. Herein, we review the emerging evidence that directly implicates Panx-1 channels in the neuroinflammatory response in the CNS. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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64 pages, 3277 KiB

Open AccessReview

Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease

by Antonio Rodríguez-Sinovas, Jose Antonio Sánchez, Laura Valls-Lacalle, Marta Consegal and Ignacio Ferreira-González

Int. J. Mol. Sci. 2021, 22(9), 4413; https://doi.org/10.3390/ijms22094413 - 23 Apr 2021

Cited by 61 | Viewed by 8483

Abstract

Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved [...] Read more.

Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions. Opening of unopposed hemichannels, located at the lateral surface of cardiomyocytes, may compromise cell homeostasis and may be involved in ischemia/reperfusion injury. In addition, connexins located at non-canonical cell structures, including mitochondria and the nucleus, have been demonstrated to be involved in cardioprotection and in regulation of cell growth and differentiation. In this review, we will provide, first, an overview on connexin biology, including their synthesis and degradation, their regulation and their interactions. Then, we will conduct an in-depth examination of the role of connexins in cardiac pathophysiology, including new findings regarding their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription or signaling regulation. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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14 pages, 1038 KiB

Open AccessReview

Mechanisms Underlying Connexin Hemichannel Activation in Disease

by Raf Van Campenhout, Ana Rita Gomes, Timo W.M. De Groof, Serge Muyldermans, Nick Devoogdt and Mathieu Vinken

Int. J. Mol. Sci. 2021, 22(7), 3503; https://doi.org/10.3390/ijms22073503 - 28 Mar 2021

Cited by 40 | Viewed by 4900

Abstract

Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the “good guys” by controlling homeostasis, connexin hemichannels are considered as the “bad guys”, as their activation is associated with the onset and dissemination of disease. [...] Read more.

Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the “good guys” by controlling homeostasis, connexin hemichannels are considered as the “bad guys”, as their activation is associated with the onset and dissemination of disease. Open connexin hemichannels indeed mediate the transport of messengers between the cytosol and extracellular environment and, by doing so, fuel inflammation and cell death in a plethora of diseases. The present mini-review discusses the mechanisms involved in the activation of connexin hemichannels during pathology. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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19 pages, 1725 KiB

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An Update on Connexin Gap Junction and Hemichannels in Diabetic Retinopathy

by Jorge González-Casanova, Oliver Schmachtenberg, Agustín D. Martínez, Helmuth A. Sanchez, Paloma A. Harcha and Diana Rojas-Gomez

Int. J. Mol. Sci. 2021, 22(6), 3194; https://doi.org/10.3390/ijms22063194 - 21 Mar 2021

Cited by 18 | Viewed by 4170

Abstract

Diabetic retinopathy (DR) is one of the main causes of vision loss in the working age population. It is characterized by a progressive deterioration of the retinal microvasculature, caused by long-term metabolic alterations inherent to diabetes, leading to a progressive loss of retinal [...] Read more.

Diabetic retinopathy (DR) is one of the main causes of vision loss in the working age population. It is characterized by a progressive deterioration of the retinal microvasculature, caused by long-term metabolic alterations inherent to diabetes, leading to a progressive loss of retinal integrity and function. The mammalian retina presents an orderly layered structure that executes initial but complex visual processing and analysis. Gap junction channels (GJC) forming electrical synapses are present in each retinal layer and contribute to the communication between different cell types. In addition, connexin hemichannels (HCs) have emerged as relevant players that influence diverse physiological and pathological processes in the retina. This article highlights the impact of diabetic conditions on GJC and HCs physiology and their involvement in DR pathogenesis. Microvascular damage and concomitant loss of endothelial cells and pericytes are related to alterations in gap junction intercellular communication (GJIC) and decreased connexin 43 (Cx43) expression. On the other hand, it has been shown that the expression and activity of HCs are upregulated in DR, becoming a key element in the establishment of proinflammatory conditions that emerge during hyperglycemia. Hence, novel connexin HCs blockers or drugs to enhance GJIC are promising tools for the development of pharmacological interventions for diabetic retinopathy, and initial in vitro and in vivo studies have shown favorable results in this regard. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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24 pages, 2510 KiB

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How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

by Roberto Zefferino, Claudia Piccoli, Sante Di Gioia, Nazzareno Capitanio and Massimo Conese

Int. J. Mol. Sci. 2021, 22(5), 2550; https://doi.org/10.3390/ijms22052550 - 4 Mar 2021

Cited by 14 | Viewed by 3974

Abstract

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with [...] Read more.

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: “Activating Invasion and Metastasis” and the “Avoiding Immune Destruction”, with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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21 pages, 2756 KiB

Open AccessReview

Connexins during 500 Million Years—From Cyclostomes to Mammals

by Svein-Ole Mikalsen, Sunnvør í Kongsstovu and Marni Tausen

Int. J. Mol. Sci. 2021, 22(4), 1584; https://doi.org/10.3390/ijms22041584 - 4 Feb 2021

Cited by 9 | Viewed by 2733

Abstract

It was previously shown that the connexin gene family had relatively similar subfamily structures in several vertebrate groups. Still, many details were left unclear. There are essentially no data between tunicates, which have connexins that cannot be divided into the classic subfamilies, and [...] Read more.

It was previously shown that the connexin gene family had relatively similar subfamily structures in several vertebrate groups. Still, many details were left unclear. There are essentially no data between tunicates, which have connexins that cannot be divided into the classic subfamilies, and teleosts, where the subfamilies are easily recognized. There are also relatively few data for the groups that diverged between the teleosts and mammals. As many of the previously analyzed genomes have been improved, and many more genomes are available, we reanalyzed the connexin gene family and included species from all major vertebrate groups. The major results can be summarized as follows: (i) The same connexin subfamily structures are found in all Gnathostomata (jawed vertebrates), with some variations due to genome duplications, gene duplications and gene losses. (ii) In contrast to previous findings, birds do not have a lower number of connexins than other tetrapods. (iii) The cyclostomes (lampreys and hagfishes) possess genes in the alpha, beta, gamma and delta subfamilies, but only some of the genes show a phylogenetic affinity to specific genes in jawed vertebrates. Thus, two major evolutionary transformations have occurred in this gene family, from tunicates to cyclostomes and from cyclostomes to jawed vertebrates. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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11 pages, 855 KiB

Open AccessReview

Function of Connexin-43 in Macrophages

by Daniel Rodjakovic, Lilian Salm and Guido Beldi

Int. J. Mol. Sci. 2021, 22(3), 1412; https://doi.org/10.3390/ijms22031412 - 30 Jan 2021

Cited by 19 | Viewed by 4236

Abstract

Recent studies have helped to increase the understanding of the function of Connexin-43 (Cx43) in macrophages (Mφ). The various roles of Cx43 in Mφs range from migration, antigen-presentation and some forms of intercellular communication to more delicate processes, such as electrochemical support in [...] Read more.

Recent studies have helped to increase the understanding of the function of Connexin-43 (Cx43) in macrophages (Mφ). The various roles of Cx43 in Mφs range from migration, antigen-presentation and some forms of intercellular communication to more delicate processes, such as electrochemical support in the propagation of the heartbeat, immunomodulatory regulation in the lungs and in macrophage-differentiation. Its relevance in pathophysiology becomes evident in inflammatory bowel disease (IBD), tumours and HIV, in which aberrant functioning of Cx43 has been described. However, the involvement of Cx43 in other Mφ functions, such as phagocytosis and polarisation, and its involvement in other types of local and systemic inflammation, are still unclear and need further research. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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17 pages, 1002 KiB

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Importance of Cx43 for Right Ventricular Function

by Kerstin Boengler, Susanne Rohrbach, Norbert Weissmann and Rainer Schulz

Int. J. Mol. Sci. 2021, 22(3), 987; https://doi.org/10.3390/ijms22030987 - 20 Jan 2021

Cited by 22 | Viewed by 4203

Abstract

In the heart, connexins form gap junctions, hemichannels, and are also present within mitochondria, with connexin 43 (Cx43) being the most prominent connexin in the ventricles. Whereas the role of Cx43 is well established for the healthy and diseased left ventricle, less is [...] Read more.

In the heart, connexins form gap junctions, hemichannels, and are also present within mitochondria, with connexin 43 (Cx43) being the most prominent connexin in the ventricles. Whereas the role of Cx43 is well established for the healthy and diseased left ventricle, less is known about the importance of Cx43 for the development of right ventricular (RV) dysfunction. The present article focusses on the importance of Cx43 for the developing heart. Furthermore, we discuss the expression and localization of Cx43 in the diseased RV, i.e., in the tetralogy of Fallot and in pulmonary hypertension, in which the RV is affected, and RV hypertrophy and failure occur. We will also introduce other Cx molecules that are expressed in RV and surrounding tissues and have been reported to be involved in RV pathophysiology. Finally, we highlight therapeutic strategies aiming to improve RV function in pulmonary hypertension that are associated with alterations of Cx43 expression and function. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)

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