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Connexins, Innexins, and Pannexins: From Biology to Clinical Targets
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Connexins, Innexins, and Pannexins: From Biology to Clinical Targets

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 72902

Special Issue Editor

Dr. Trond Aasen

E-Mail Website
Guest Editor
1. Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
2. CIBER de Cáncer (CIBERONC), Instituto de Salud Carlos III, Avenida de Monforte de Lemos 3-5, 28029 Madrid, Spain
3. Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Interests: gap junctions; connexins; pannexins; cell–cell communication; mRNA translation; cell signaling; cancer; cell biology; pathophysiology

Special Issue Information

Dear Colleagues,

Direct intercellular communication via gap junction channels allows for the exchange of small molecules between cells, including ions, metabolites, second messengers, small peptides, and even microRNAs. A large family of connexin proteins facilitate this syncytium between cells, which is deemed critical for tissue development and tissue homeostasis. In addition, under certain pathophysiological conditions, connexin hemichannels open to allow for direct exchange between cells and the extracellular milieu. Furthermore, new insight has identified a myriad of non-canonical connexin functions, including as signaling hubs, as components of mitochondria, and as regulators of extracellular vesicle biology. The direct translation of truncated connexin forms has added another layer of complexity to this puzzle.

Non-chordates, such as flatworms and Drosophila, utilize the innexin protein family for a similar purpose. More recently, pannexin proteins were discovered in vertebrates due to their homology to innexins, but were subsequently found to predominantly act as transmembrane channels that connect the intracellular and extracellular space.

The field of connexins, innexins, and pannexins is evolving rapidly through the discovery of new biological functions and phenotypic associations. This new insight is bringing about novel therapeutic opportunities to tackle some of the associated diseases, which include deafness, blindness, skin disease, cancer, cardiovascular disease, and a wide variety of neurological disorders and complex syndromic diseases.

The contributions of reviews and original articles to this Special Issue are intended to provide insight and to shed light on various aspects of this multidisciplinary and exciting field of research.

Dr. Trond Aasen
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • connexins
  • gap junctions
  • cell–cell communication
  • pannexins
  • innexins
  • channel biology
  • peptide therapy
  • tissue homeostasis and disease
  • membrane biology

Published Papers (22 papers)

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Editorial

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5 pages, 216 KiB  
Editorial
Connexins, Innexins, and Pannexins: From Biology to Clinical Targets
by Trond Aasen
Biomolecules 2021, 11(2), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020155 - 25 Jan 2021
Cited by 2 | Viewed by 1913
Abstract
In 1964, Loewenstein and Kanno [...] Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)

Research

Jump to: Editorial, Review

15 pages, 2286 KiB  
Article
Functional Evaluation of a Rare Variant c.516G>C (p.Trp172Cys) in the GJB2 (Connexin 26) Gene Associated with Nonsyndromic Hearing Loss
by Ekaterina A. Maslova, Konstantin E. Orishchenko and Olga L. Posukh
Biomolecules 2021, 11(1), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010061 - 05 Jan 2021
Cited by 7 | Viewed by 3130
Abstract
Mutations in the GJB2 gene encoding transmembrane protein connexin 26 (Cx26) are the most common cause for hearing loss worldwide. Cx26 plays a crucial role in the ionic and metabolic homeostasis in the inner ear, indispensable for normal hearing process. Different pathogenic mutations [...] Read more.
Mutations in the GJB2 gene encoding transmembrane protein connexin 26 (Cx26) are the most common cause for hearing loss worldwide. Cx26 plays a crucial role in the ionic and metabolic homeostasis in the inner ear, indispensable for normal hearing process. Different pathogenic mutations in the GJB2 gene can affect all stages of the Cx26 life cycle and result in nonsyndromic autosomal recessive (DFNB1) or dominant (DFNA3) deafness and syndromes associating hearing loss with skin disorders. This study aims to elucidate the functional consequences of a rare GJB2 variant c.516G>C (p.Trp172Cys) found with high frequency in deaf patients from indigenous populations of Southern Siberia (Russia). The substitution c.516G>C leads to the replacement of tryptophan at a conserved amino acid position 172 with cysteine (p.Trp172Cys) in the second extracellular loop of Cx26 protein. We analyzed the subcellular localization of mutant Cx26-p.Trp172Cys protein by immunocytochemistry and the hemichannels permeability by dye loading assay. The GJB2 knockout HeLa cell line has been generated using CRISPR/Cas9 genome editing tool. Subsequently, the HeLa transgenic cell lines stably expressing different GJB2 variants (wild type and mutations associated with hearing loss) were established based on knockout cells and used for comparative functional analysis. The impaired trafficking of mutant Cx26-p.Trp172Cys protein to the plasma membrane and reduced hemichannels permeability support the pathogenic effect of the c.516G>C (p.Trp172Cys) variant and its association with nonsyndromic hearing loss. Our data contribute to a better understanding of the role of mutations in the second extracellular loop of Cx26 protein in pathogenesis of deafness. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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15 pages, 5871 KiB  
Article
A Limited and Diverse Set of Suppressor Mutations Restore Function to INX-8 Mutant Hemichannels in the Caenorhabditis elegans Somatic Gonad
by Todd Starich and David Greenstein
Biomolecules 2020, 10(12), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10121655 - 10 Dec 2020
Cited by 2 | Viewed by 2394
Abstract
In Caenorhabditis elegans, gap junctions couple cells of the somatic gonad with the germline to support germ cell proliferation and gametogenesis. A strong loss-of-function mutation (T239I) affects the second extracellular loop (EL2) of the somatic INX-8 hemichannel subunit. These mutant hemichannels form [...] Read more.
In Caenorhabditis elegans, gap junctions couple cells of the somatic gonad with the germline to support germ cell proliferation and gametogenesis. A strong loss-of-function mutation (T239I) affects the second extracellular loop (EL2) of the somatic INX-8 hemichannel subunit. These mutant hemichannels form non-functional gap junctions with germline-expressed innexins. We conducted a genetic screen for suppressor mutations that restore germ cell proliferation in the T239I mutant background and isolated seven intragenic mutations, located in diverse domains of INX-8 but not the EL domains. These second-site mutations compensate for the original channel defect to varying degrees, from nearly complete wild-type rescue, to partial rescue of germline proliferation. One suppressor mutation (E350K) supports the innexin cryo-EM structural model that the channel pore opening is surrounded by a cytoplasmic dome. Two suppressor mutations (S9L and I36N) may form leaky channels that support germline proliferation but cause the demise of somatic sheath cells. Phenotypic analyses of three of the suppressors reveal an equivalency in the rescue of germline proliferation and comparable delays in gametogenesis but a graded rescue of fertility. The mutations described here may be useful for elucidating the biochemical pathways that produce the active biomolecules transiting through soma–germline gap junctions. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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18 pages, 3719 KiB  
Article
Src Regulation of Cx43 Phosphorylation and Gap Junction Turnover
by Joell L. Solan and Paul D. Lampe
Biomolecules 2020, 10(12), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10121596 - 24 Nov 2020
Cited by 23 | Viewed by 2762
Abstract
The gap junction protein Connexin43 (Cx43) is highly regulated by phosphorylation at over a dozen sites by probably at least as many kinases. This Cx43 “kinome” plays an important role in gap junction assembly and turnover. We sought to gain a better understanding [...] Read more.
The gap junction protein Connexin43 (Cx43) is highly regulated by phosphorylation at over a dozen sites by probably at least as many kinases. This Cx43 “kinome” plays an important role in gap junction assembly and turnover. We sought to gain a better understanding of the interrelationship of these phosphorylation events particularly related to src activation and Cx43 turnover. Using state-of-the-art live imaging methods, specific inhibitors and many phosphorylation-status specific antibodies, we found phospho-specific domains in gap junction plaques and show evidence that multiple pathways of disassembly exist and can be regulated at the cellular and subcellular level. We found Src activation promotes formation of connexisomes (internalized gap junctions) in a process involving ERK-mediated phosphorylation of S279/282. Proteasome inhibition dramatically and rapidly restored gap junctions in the presence of Src and led to dramatic changes in the Cx43 phospho-profile including to increased Y247, Y265, S279/282, S365, and S373 phosphorylation. Lysosomal inhibition, on the other hand, nearly eliminated phosphorylation on Y247 and Y265 and reduced S368 and S373 while increasing S279/282 phosphorylation levels. We present a model of gap junction disassembly where multiple modes of disassembly are regulated by phosphorylation and can have differential effects on cellular signaling. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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23 pages, 6204 KiB  
Article
Calmodulin Directly Interacts with the Cx43 Carboxyl-Terminus and Cytoplasmic Loop Containing Three ODDD-Linked Mutants (M147T, R148Q, and T154A) that Retain α-Helical Structure, but Exhibit Loss-of-Function and Cellular Trafficking Defects
by Li Zheng, Sylvie Chenavas, Fabien Kieken, Andrew Trease, Sarah Brownell, Asokan Anbanandam, Paul L. Sorgen and Gaelle Spagnol
Biomolecules 2020, 10(10), 1452; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101452 - 17 Oct 2020
Cited by 6 | Viewed by 2908
Abstract
The autosomal-dominant pleiotropic disorder called oculodentodigital dysplasia (ODDD) is caused by mutations in the gap junction protein Cx43. Of the 73 mutations identified to date, over one-third are localized in the cytoplasmic loop (Cx43CL) domain. Here, we determined the mechanism by which three [...] Read more.
The autosomal-dominant pleiotropic disorder called oculodentodigital dysplasia (ODDD) is caused by mutations in the gap junction protein Cx43. Of the 73 mutations identified to date, over one-third are localized in the cytoplasmic loop (Cx43CL) domain. Here, we determined the mechanism by which three ODDD mutations (M147T, R148Q, and T154A), all of which localize within the predicted 1-5-10 calmodulin-binding motif of the Cx43CL, manifest the disease. Nuclear magnetic resonance (NMR) and circular dichroism revealed that the three ODDD mutations had little-to-no effect on the ability of the Cx43CL to form α-helical structure as well as bind calmodulin. Combination of microscopy and a dye-transfer assay uncovered these mutations increased the intracellular level of Cx43 and those that trafficked to the plasma membrane did not form functional channels. NMR also identify that CaM can directly interact with the Cx43CT domain. The Cx43CT residues involved in the CaM interaction overlap with tyrosines phosphorylated by Pyk2 and Src. In vitro and in cyto data provide evidence that the importance of the CaM interaction with the Cx43CT may lie in restricting Pyk2 and Src phosphorylation, and their subsequent downstream effects. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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20 pages, 11431 KiB  
Article
Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes
by Akina Au, Qing Shao, Kyra K. White, Sergiu A. Lucaciu, Jessica L. Esseltine, Kevin Barr and Dale W. Laird
Biomolecules 2020, 10(10), 1443; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101443 - 14 Oct 2020
Cited by 9 | Viewed by 2542
Abstract
When considering connexin expression and regulation, the epidermis of the skin is one of the most complex tissues found in mammals even though it largely contains a single cell type, the keratinocyte. In the rodent epidermis, up to 9 connexin family members have [...] Read more.
When considering connexin expression and regulation, the epidermis of the skin is one of the most complex tissues found in mammals even though it largely contains a single cell type, the keratinocyte. In the rodent epidermis, up to 9 connexin family members have been detected at the mRNA level. Many of these connexins are temporally and spatially regulated in coordination with keratinocyte progenitor cell differentiation and migration from the stratum basale to form the stratum spinosum and stratum granulosum layers before finally forming the stratum corneum. Cx43 is the principal connexin found in basal keratinocytes and to a lesser degree found in keratinocytes that have begun to differentiate where Cx26, Cx30 and Cx31 become prevalent. Here we show that the CRISPR-Cas9 ablation of Cx43 reduces overall gap junction coupling in monolayer cultures of rat epidermal keratinocytes (REKs) and dysregulates the differentiation of REKs when grown in organotypic cultures. Natively found in differentiated keratinocytes, Cx31 readily assembles into gap junctions when expressed in REKs where it can extensively co-assemble into the same gap junctions with co-expressed Cx30. Time-lapse imaging indicated that many Cx31 gap junctions are mobile within the plasma membrane undergoing both fusion and fission events. Finally, the persistence of pre-existing Cx31 gap junctions in the presence of the protein trafficking blocker, brefeldin A, is longer than that found for Cx43 gap junctions indicating that it has a distinctly different life expectancy in REKs. Collectively, this study highlights the importance of Cx43 in rodent keratinocyte differentiation and suggests that Cx31 acquires life-cycle properties that are distinct from Cx43. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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21 pages, 4075 KiB  
Article
Effects of Elevated Downstream Pressure and the Role of Smooth Muscle Cell Coupling through Connexin45 on Lymphatic Pacemaking
by Jorge A. Castorena-Gonzalez, Min Li and Michael J. Davis
Biomolecules 2020, 10(10), 1424; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101424 - 08 Oct 2020
Cited by 7 | Viewed by 2203
Abstract
Lymphatic vessels rely on spontaneous lymphatic muscle cell (LMC) contractions and one-way intraluminal valves to efficiently pump lymph and return it into the bloodstream. Intraluminal pressure is known to regulate the contractile function of lymphatics, with pressure elevation leading to increased contraction frequency [...] Read more.
Lymphatic vessels rely on spontaneous lymphatic muscle cell (LMC) contractions and one-way intraluminal valves to efficiently pump lymph and return it into the bloodstream. Intraluminal pressure is known to regulate the contractile function of lymphatics, with pressure elevation leading to increased contraction frequency and decreased amplitude. Contractions are normally initiated by a dominant pacemaker and are highly entrained among strongly coupled LMCs. Previously, we found that connexin45 is the major connexin isoform mediating LMC-LMC electrical coupling. Lymphatics from mice lacking smooth muscle connexin45 display uncoordinated, impaired contractions. Here, we utilized this connexin45-deficient model, pressure myography, and recently developed, novel analytical tools to assess the effects of elevated downstream pressure on the number, location, and frequency of lymphatic pacemakers. Our results show that, in vessels from healthy controls, an increase in downstream pressure resulted in the recruitment/development of new pacemakers and increased contractile frequency while a dominant pacemaker continued to be observed. In contrast, vessels from connexin45-deficient mice displayed significantly more pacemakers, but none were dominant; this worsened with elevated downstream pressure. These results suggest a potential protective mechanism through which the lymphatic vasculature adapts to transient increases in downstream pressure, but which may not be sustained in scenarios with chronic elevated downstream pressure. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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14 pages, 1885 KiB  
Article
Do Connexin Mutants Cause Cataracts by Perturbing Glutathione Levels and Redox Metabolism in the Lens?
by Oscar Jara, Peter J. Minogue, Viviana M. Berthoud and Eric C. Beyer
Biomolecules 2020, 10(10), 1418; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101418 - 07 Oct 2020
Cited by 8 | Viewed by 2075
Abstract
Cataracts of many different etiologies are associated with oxidation of lens components. The lens is protected by maintenance of a pool of reduced glutathione (GSH) and other antioxidants. Because gap junction channels made of the lens connexins, Cx46 and Cx50, are permeable to [...] Read more.
Cataracts of many different etiologies are associated with oxidation of lens components. The lens is protected by maintenance of a pool of reduced glutathione (GSH) and other antioxidants. Because gap junction channels made of the lens connexins, Cx46 and Cx50, are permeable to GSH, we tested whether mice expressing two different mutants, Cx46fs380 and Cx50D47A, cause cataracts by impairing lens glutathione metabolism and facilitating oxidative damage. Levels of GSH were not reduced in homogenates of whole mutant lenses. Oxidized glutathione (GSSG) and the GSSG/GSH ratio were increased in whole lenses of Cx50D47A, but not Cx46fs380 mice. The GSSG/GSH ratio was increased in the lens nucleus (but not cortex) of Cx46fs380 mice at 4.5 months of age, but it was not altered in younger animals. Carbonylated proteins were increased in Cx50D47A, but not Cx46fs380 lenses. Thus, both mouse lines have oxidizing lens environments, but oxidative modification is greater in Cx50D47A than in Cx46fs380 mice. The results suggest that GSH permeation through lens connexin channels is not a critical early event in cataract formation in these mice. Moreover, because oxidative damage was only detected in animals with significant cataracts, it cannot be an early event in their cataractogenesis. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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15 pages, 2342 KiB  
Article
Confirmation of Connexin45 Underlying Weak Gap Junctional Intercellular Coupling in HeLa Cells
by Eun Ju Choi, Nicolás Palacios-Prado, Juan C. Sáez and Jinu Lee
Biomolecules 2020, 10(10), 1389; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101389 - 29 Sep 2020
Cited by 11 | Viewed by 2597
Abstract
Gap junctions (GJs) are intercellular channels that connect adjacent cells electrically and metabolically. The iodide-yellow fluorescent protein (I-YFP) gap junctional intercellular communication (GJIC) assay is a recently developed method with high sensitivity. HeLa cells have been widely used as GJ-deficient cells for GJ-related [...] Read more.
Gap junctions (GJs) are intercellular channels that connect adjacent cells electrically and metabolically. The iodide-yellow fluorescent protein (I-YFP) gap junctional intercellular communication (GJIC) assay is a recently developed method with high sensitivity. HeLa cells have been widely used as GJ-deficient cells for GJ-related research. Herein, we present evidence showing that HeLa cells have functional GJs comprising connexin (Cx) 45 using the I-YFP GJ assay and CRISPR/Cas9 system. We conducted the I-YFP GJIC assay in HeLa cells, which revealed a weak level of GJIC that could not be detected by the Lucifer yellow scrape-loading assay. The mRNA expression of GJB5 (Cx31.1), GJA1 (Cx43), and GJC1 (Cx45) was detected in HeLa cells by RT-PCR analysis. Knocking out GJC1 (Cx45) abolished GJIC, as analyzed by the I-YFP assay and dual whole-cell patch-clamp assay. These results suggest that HeLa cells express Cx45-based GJs and that the I-YFP GJIC assay can be used for cells with weak GJIC, such as Cx45-expressing HeLa cells. Further, GJC1 (Cx45)-knockout HeLa cells are more suitable as a GJ-null cell model for transfection experiments than wild-type HeLa cells. This experimental design was successfully applied to knock out Cx43 expression and GJIC in A549 lung cancer cells and can thus be used to identify major Cxs in other cell types and to establish GJ assay systems for different Cxs. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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Graphical abstract

25 pages, 26408 KiB  
Article
Automatic Quantification of Cardiomyocyte Dimensions and Connexin 43 Lateralization in Fluorescence Images
by Antoni Oliver-Gelabert, Laura García-Mendívil, José María Vallejo-Gil, Pedro Carlos Fresneda-Roldán, Katarína Andelová, Javier Fañanás-Mastral, Manuel Vázquez-Sancho, Marta Matamala-Adell, Fernando Sorribas-Berjón, Carlos Ballester-Cuenca, Narcisa Tribulova, Laura Ordovás, Emiliano Raúl Diez and Esther Pueyo
Biomolecules 2020, 10(9), 1334; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10091334 - 17 Sep 2020
Cited by 6 | Viewed by 3935
Abstract
Cardiomyocytes’ geometry and connexin 43 (CX43) amount and distribution are structural features that play a pivotal role in electrical conduction. Their quantitative assessment is of high interest in the study of arrhythmias, but it is usually hampered by the lack of automatic tools. [...] Read more.
Cardiomyocytes’ geometry and connexin 43 (CX43) amount and distribution are structural features that play a pivotal role in electrical conduction. Their quantitative assessment is of high interest in the study of arrhythmias, but it is usually hampered by the lack of automatic tools. In this work, we propose a software algorithm (Myocyte Automatic Retrieval and Tissue Analyzer, MARTA) to automatically detect myocytes from fluorescent microscopy images of cardiac tissue, measure their morphological features and evaluate the expression of CX43 and its degree of lateralization. The proposed software is based on the generation of cell masks, contouring of individual cells, enclosing of cells in minimum area rectangles and splitting of these rectangles into end-to-end and middle compartments to estimate CX43 lateral-to-total ratio. Application to human ventricular tissue images shows that mean differences between automatic and manual methods in terms of cardiomyocyte length and width are below 4 μm. The percentage of lateral CX43 also agrees between automatic and manual evaluation, with the interquartile range approximately covering from 3% to 30% in both cases. MARTA is not limited by fiber orientation and has an optimized speed by using contour filtering, which makes it run hundreds of times faster than a trained expert. Developed for CX43 studies in the left ventricle, MARTA is a flexible tool applicable to morphometric and lateralization studies of other markers in any heart chamber or even skeletal muscle. This open-access software is available online. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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18 pages, 5182 KiB  
Article
Connexin-46 Contained in Extracellular Vesicles Enhance Malignancy Features in Breast Cancer Cells
by Rodrigo A. Acuña, Manuel Varas-Godoy, Viviana M. Berthoud, Ivan E. Alfaro and Mauricio A. Retamal
Biomolecules 2020, 10(5), 676; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050676 - 28 Apr 2020
Cited by 20 | Viewed by 3807
Abstract
Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six [...] Read more.
Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six subunits of transmembrane proteins called connexins (Cx). For many years, it was believed that the loss of GJC-mediated intercellular communication was a hallmark in cancer development. However, nowadays this paradigm is changing. The connexin 46 (Cx46), which is almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and is correlated with tumor growth in a Xenograft mouse model. On the other hand, extracellular vesicles (EVs) have an important role in long-distance communication under physiological conditions. In the last decade, EVs also have been recognized as key players in cancer aggressiveness. The aim of this work was to explore the involvement of Cx46 in EV-mediated intercellular communication. Here, we demonstrated for the first time, that Cx46 is contained in EVs released from breast cancer cells overexpressing Cx46 (EVs-Cx46). This EV-Cx46 facilitates the interaction between EVs and the recipient cell resulting in an increase in their migration and invasion properties. Our results suggest that EV-Cx46 could be a marker of cancer malignancy and open the possibility to consider Cx46 as a new therapeutic target in cancer treatment. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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10 pages, 2039 KiB  
Article
Connexin 43 Deficiency Is Associated with Reduced Myocardial Scar Size and Attenuated TGFβ1 Signaling after Transient Coronary Occlusion in Conditional Knock-Out Mice
by Laura Valls-Lacalle, Marta Consegal, Marisol Ruiz-Meana, Begoña Benito, Javier Inserte, Ignasi Barba, Ignacio Ferreira-González and Antonio Rodríguez-Sinovas
Biomolecules 2020, 10(4), 651; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040651 - 23 Apr 2020
Cited by 8 | Viewed by 2710
Abstract
Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43+/- mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed [...] Read more.
Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43+/- mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43fl/fl (controls) and Cx43Cre-ER(T)/fl inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. The scar area (picrosirius red), measured 14 days after transient coronary occlusion, was similarly reduced in both vehicle and 4-OHT-treated Cx43Cre-ER(T)/fl mice, compared to Cx43fl/fl animals, having normal Cx43 levels (15.78% ± 3.42% and 16.54% ± 2.31% vs. 25.40% ± 3.14% and 22.43% ± 3.88% in vehicle and 4-OHT-treated mice, respectively, p = 0.027). Left ventricular dilatation was significantly attenuated in both Cx43-deficient groups (p = 0.037 for left ventricular end-diastolic diameter). These protective effects were correlated with an attenuated enhancement in pro-transforming growth factor beta 1 (TGFβ1) expression after reperfusion. In conclusion, our data demonstrate that Cx43 deficiency induces a protective effect on scar formation after transient coronary occlusion in mice, an effect associated with reduced left ventricular remodeling and attenuated enhancement in pro-TGFβ1 expression. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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12 pages, 1363 KiB  
Article
Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice
by Moises Freitas-Andrade, John Bechberger, Jasmine Wang, Ken K.C. Yeung, Shawn N. Whitehead, Rie Shultz Hansen and Christian C. Naus
Biomolecules 2020, 10(3), 353; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030353 - 26 Feb 2020
Cited by 17 | Viewed by 3370
Abstract
Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential [...] Read more.
Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential target for therapeutic approaches to stroke. We examined the effect of danegaptide (ZP1609), an antiarrhythmic dipeptide that specifically enhances GJ conductance, in two different rodent stroke models. In this study, danegaptide increased astrocytic Cx43 coupling with no significant effects on Cx43 hemichannel activity, in vitro. Using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) the presence of danegaptide within brain tissue sections were detected one hour after reperfusion indicating successful transport of the dipeptide across the blood brain barrier. Furthermore, administration of danegaptide in a novel mouse brain ischemia/reperfusion model showed significant decrease in infarct volume. Taken together, this study provides evidence for the therapeutic potential of danegaptide in ischemia/reperfusion stroke. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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15 pages, 2358 KiB  
Article
Role of an Aromatic–Aromatic Interaction in the Assembly and Trafficking of the Zebrafish Panx1a Membrane Channel
by Ksenia Timonina, Anna Kotova and Georg Zoidl
Biomolecules 2020, 10(2), 272; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020272 - 11 Feb 2020
Cited by 4 | Viewed by 2862
Abstract
Pannexin 1 (Panx1) is a ubiquitously expressed hexameric integral membrane protein known to function as an adenosine triphosphate (ATP) release channel. Panx1 proteins exist in unglycosylated core form (Gly0). They undergo critical post-translational modifications forming the high mannose glycosylation state (Gly1) in the [...] Read more.
Pannexin 1 (Panx1) is a ubiquitously expressed hexameric integral membrane protein known to function as an adenosine triphosphate (ATP) release channel. Panx1 proteins exist in unglycosylated core form (Gly0). They undergo critical post-translational modifications forming the high mannose glycosylation state (Gly1) in the endoplasmic reticulum (ER) and the complex glycosylation state (Gly2) in the Golgi apparatus. The regulation of transition from the ER to the cell membrane is not fully understood. Using site-specific mutagenesis, dye uptake assays, and interaction testing, we identified two conserved aromatic residues, Trp123 and Tyr205, in the transmembrane domains 2 and 3 of the zebrafish panx1a protein. Results suggest that both residues primarily govern the assembly of panx1a subunits into channels, with mutant proteins failing to interact. The results provide insight into a mechanism enabling regulation of Panx1 oligomerization, glycosylation, and trafficking. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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14 pages, 3494 KiB  
Article
A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI
by Filippo Molica, Alessandra Quercioli, Fabrizio Montecucco, Thomas H. Schindler, Brenda R. Kwak and Sandrine Morel
Biomolecules 2020, 10(2), 208; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020208 - 31 Jan 2020
Cited by 2 | Viewed by 2352
Abstract
Endothelial dysfunction worsens when body mass index (BMI) increases. Pannexin1 (Panx1) ATP release channels regulate endothelial function and lipid homeostasis in mice. We investigated whether the Panx1-400A>C single nucleotide polymorphism (SNP), encoding for a gain-of-function channel, associates with endothelial dysfunction in non-obese and [...] Read more.
Endothelial dysfunction worsens when body mass index (BMI) increases. Pannexin1 (Panx1) ATP release channels regulate endothelial function and lipid homeostasis in mice. We investigated whether the Panx1-400A>C single nucleotide polymorphism (SNP), encoding for a gain-of-function channel, associates with endothelial dysfunction in non-obese and obese individuals. Myocardial blood flow (MBF) was measured by 13N-ammonia positron emission/computed tomography at rest, during cold pressor test (CPT) or dipyridamole-induced hyperemia. Myocardial flow reserve (MFR) and endothelial function were compared in 43 non-obese (BMI < 30 kg/m2) vs. 29 obese (BMI ≥ 30 kg/m2) participants and genotyping for the Panx1-400A>C SNP was performed. Groups comprised subjects homozygous for the C allele (n = 40) vs. subjects with at least one A allele (n = 32). MBF (during CPT or hyperemia), MFR and endothelial function correlated negatively with BMI in the full cohort. BMI correlated negatively with MFR and endothelial function in non-obese Panx1-400C subjects, but not in Panx1-400A individuals nor in obese groups. BMI correlated positively with serum triglycerides, insulin or HOMA. MFR correlated negatively with these factors in non-obese Panx1-400C but not in Panx1-400A individuals. Here, we demonstrated that Panx1-400C SNP predisposes to BMI-dependent endothelial dysfunction in non-obese subjects. This effect may be masked by excessive dysregulation of metabolic factors in obese individuals. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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16 pages, 2509 KiB  
Article
Connexin43 is Dispensable for Early Stage Human Mesenchymal Stem Cell Adipogenic Differentiation But is Protective against Cell Senescence
by Qing Shao, Jessica L. Esseltine, Tao Huang, Nicole Novielli-Kuntz, Jamie E. Ching, Jacinda Sampson and Dale W. Laird
Biomolecules 2019, 9(9), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090474 - 11 Sep 2019
Cited by 14 | Viewed by 4756
Abstract
In the last couple of decades, there has been a growing optimism surrounding the potential transformative use of human mesenchymal stem cells (MSCs) and human-induced pluripotent stem cells (iPSCs) for regenerative medicine and disease treatment. In order for this to occur, it is [...] Read more.
In the last couple of decades, there has been a growing optimism surrounding the potential transformative use of human mesenchymal stem cells (MSCs) and human-induced pluripotent stem cells (iPSCs) for regenerative medicine and disease treatment. In order for this to occur, it is first essential to understand the mechanisms underpinning their cell-fate specification, which includes cell signaling via gap junctional intercellular communication. Here, we investigated the role of the prototypical gap junction protein, connexin43 (Cx43), in governing the differentiation of iPSCs into MSCs and MSC differentiation along the adipogenic lineage. We found that control iPSCs, as well as iPSCs derived from oculodentodigital dysplasia patient fibroblasts harboring a GJA1 (Cx43) gene mutation, successfully and efficiently differentiated into LipidTox and perilipin-positive cells, indicating cell differentiation along the adipogenic lineage. Furthermore, the complete CRISPR-Cas9 ablation of Cx43 from iPSCs did not prevent their differentiation into bona fide MSCs or pre-adipocytes, strongly suggesting that even though Cx43 expression is upregulated during adipogenesis, it is expendable. Interestingly, late passage Cx43-ablated MSCs senesced more quickly than control cells, resulting in failure to properly differentiate in vitro. We conclude that despite being upregulated during adipogenesis, Cx43 plays no detectable role in the early stages of human iPSC-derived MSC adipogenic differentiation. However, Cx43 may play a more impactful role in protecting MSCs from premature senescence. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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Review

Jump to: Editorial, Research

64 pages, 2862 KiB  
Review
Brain Disorders and Chemical Pollutants: A Gap Junction Link?
by Marc Mesnil, Norah Defamie, Christian Naus and Denis Sarrouilhe
Biomolecules 2021, 11(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010051 - 31 Dec 2020
Cited by 16 | Viewed by 5308
Abstract
The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson’s disease, Alzheimer’s disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain [...] Read more.
The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson’s disease, Alzheimer’s disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants. In this article, this hypothesis is addressed through three complementary aspects: (1) the gap-junctional organization and connexin expression in brain parenchyma and their function; (2) the effect of major pollutants (pesticides, bisphenol A, phthalates, heavy metals, airborne particles, etc.) on gap-junctional and connexin functions; (3) a description of the major brain disorders categorized as neurodevelopmental (autism spectrum disorders, attention deficit hyperactivity disorders, epilepsy), neurobehavioral (migraines, major depressive disorders), neurodegenerative (Parkinson’s and Alzheimer’s diseases) and cancers (glioma), in which both connexin dysfunction and pollutant involvement have been described. Based on these different aspects, the possible involvement of pollutant-inhibited gap junctions in brain disorders is discussed for prenatal and postnatal exposures. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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26 pages, 1612 KiB  
Review
Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation
by Randy E. Strauss and Robert G. Gourdie
Biomolecules 2020, 10(12), 1656; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10121656 - 10 Dec 2020
Cited by 18 | Viewed by 3994
Abstract
Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this [...] Read more.
Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers. Mounting evidence of crosstalk between connexins, the cytoskeleton, focal adhesion complexes, and junctional structures has led to a growing appreciation of how barrier-modulating mechanisms may work together to effect solute and cellular flux across tissue boundaries. This new understanding could translate into improved therapeutic outcomes in the treatment of barrier-associated diseases. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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30 pages, 1309 KiB  
Review
Connexins in Cancer: Jekyll or Hyde?
by Erin E. Mulkearns-Hubert, Ofer Reizes and Justin D. Lathia
Biomolecules 2020, 10(12), 1654; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10121654 - 10 Dec 2020
Cited by 20 | Viewed by 3531
Abstract
The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and [...] Read more.
The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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Graphical abstract

32 pages, 741 KiB  
Review
Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment
by Laura Walrave, Mathieu Vinken, Luc Leybaert and Ilse Smolders
Biomolecules 2020, 10(11), 1578; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111578 - 20 Nov 2020
Cited by 26 | Viewed by 4631
Abstract
In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 [...] Read more.
In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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23 pages, 1135 KiB  
Review
Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors
by Julie Talbot, Maryne Dupuy, Sarah Morice, Françoise Rédini and Franck Verrecchia
Biomolecules 2020, 10(9), 1240; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10091240 - 26 Aug 2020
Cited by 7 | Viewed by 3448
Abstract
Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases [...] Read more.
Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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22 pages, 2238 KiB  
Review
Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection
by Olga M. Rusiecka, Jade Montgomery, Sandrine Morel, Daniela Batista-Almeida, Raf Van Campenhout, Mathieu Vinken, Henrique Girao and Brenda R. Kwak
Biomolecules 2020, 10(9), 1225; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10091225 - 23 Aug 2020
Cited by 23 | Viewed by 4041
Abstract
Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo [...] Read more.
Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo animal models of cardiac ischemia/reperfusion (I/R) injury are robustly used in research. Connexin43 (Cx43), the predominant gap junction channel-forming protein in cardiomyocytes, has emerged as a cardioprotective target. Cx43 posttranslational modifications as well as cellular distribution are altered during cardiac reperfusion injury, inducing phosphorylation states and localization detrimental to maintaining intercellular communication and cardiac conduction. Pre- (before ischemia) and post- (after ischemia but before reperfusion) conditioning can abrogate this injury process, preserving Cx43 and reducing cell death. Pre-/post-conditioning has been shown to largely rely on the presence of Cx43, including mitochondrial Cx43, which is implicated to play a major role in pre-conditioning. Posttranslational modifications of Cx43 after injury alter the protein interactome, inducing negative protein cascades and altering protein trafficking, which then causes further damage post-I/R injury. Recently, several peptides based on the Cx43 sequence have been found to successfully diminish cardiac injury in pre-clinical studies. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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