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Biomolecules
Special Issues
Gap Junctions and Connexins in Health and Disease
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Gap Junctions and Connexins in Health and Disease

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 12651

Special Issue Editors

Prof. Dr. Béla Völgyi

E-Mail Website
Guest Editor
Retinal Neurobiology Research Group, University of Pecs, Pecs, Hungary
Interests: vision; retinal signal processing; ganglion cells; population coding; electrical synapses; parallel signaling; morphological/functional classification
Special Issues, Collections and Topics in MDPI journals
Dr. Tamas Kovacs-Oller

E-Mail Website
Guest Editor
Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary
Interests: retina; gap junction; neuronal degeneration; traumatic brain injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Connexins are pore-forming proteins incorporated in the cellular membrane where they coalesce into hexamer connexons (hemichannels). They either serve as an interface between the intracellular molecular milieu and the extracellular environment or pair up with another connexons embedded in the membrane of a neighbor cell to form intercellular passageways. This latter structure is called gap junction and allows for the transcellular movement of ions and small weight molecules. Both hemichannels and gap junctions can serve metabolic and/or electrical communication purposes for various cells in the body, and thus, they appear as essential and versatile factors in conducting many specific functions for living systems. Nevertheless, disruption or exacerbation of hemichannel and gap junction functioning are related to a number of pathological conditions, further demonstrating their essential roles in the life of living cells. Finally, gap junctions have also been proposed to distribute apoptotic factors (death signals) between connected cells. This so-called bystander effect underlies a secondary loss of cells that maintain gap junction contact with their injured neighbors even if they escape a primary harmful insult. Due to this latter feature, gap junctions have recently been identified as potential therapeutic targets in trials using pharmacological blockade, gene therapy, or electrical stimulation. This Special Issue intends to bring work from many different fields of biology together to reveal recent advances in both discovery and clinical research, with a focus on connexins and gap junctions.

Prof. Dr. Béla Völgyi
Dr. Tamás Kovács-Öller
Guest Editors

Manuscript Submission Information

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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

  • connexin
  • connexon
  • hemichannel
  • gap junction
  • electrical synapse
  • communication
  • bystander effect

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Related Special Issue

Published Papers (5 papers)

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Research

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19 pages, 3454 KiB  
Article
Regulation of Cx43 Gap Junction Intercellular Communication by Bruton’s Tyrosine Kinase and Interleukin-2-Inducible T-Cell Kinase
by Ishika Basu, Hanjun Li, Andrew J. Trease and Paul L. Sorgen
Biomolecules 2023, 13(4), 660; https://doi.org/10.3390/biom13040660 - 8 Apr 2023
Viewed by 2234
Abstract
T and B cell receptor signaling involves the activation of Akt, MAPKs, and PKC as well as an increase in intracellular Ca2+ and calmodulin activation. While these coordinate the rapid turnover of gap junctions, also implicated in this process is Src, which [...] Read more.
T and B cell receptor signaling involves the activation of Akt, MAPKs, and PKC as well as an increase in intracellular Ca2+ and calmodulin activation. While these coordinate the rapid turnover of gap junctions, also implicated in this process is Src, which is not activated as part of T and B cell receptor signaling. An in vitro kinase screen identified that Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) phosphorylate Cx43. Mass spectroscopy revealed that BTK and ITK phosphorylate Cx43 residues Y247, Y265, and Y313, which are identical to the residues phosphorylated by Src. Overexpression of BTK or ITK in the HEK-293T cells led to increased Cx43 tyrosine phosphorylation as well as decreased gap junction intercellular communication (GJIC) and Cx43 membrane localization. In the lymphocytes, activation of the B cell receptor (Daudi cells) or T cell receptor (Jurkat cells) increased the BTK and ITK activity, respectively. While this led to increased tyrosine phosphorylation of Cx43 and decreased GJIC, the cellular localization of Cx43 changed little. We have previously identified that Pyk2 and Tyk2 also phosphorylate Cx43 at residues Y247, Y265, and Y313 with a similar cellular fate to that of Src. With phosphorylation critical to Cx43 assembly and turnover, and kinase expression varying between different cell types, there would be a need for different kinases to achieve the same regulation of Cx43. The work presented herein suggests that in the immune system, ITK and BTK have the capacity for the tyrosine phosphorylation of Cx43 to alter the gap junction function in a similar manner as Pyk2, Tyk2, and Src. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease)
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12 pages, 2069 KiB  
Article
KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells
by Cheng-Wei T. Chang, Naveena Poudyal, Daniel A. Verdugo, Francisca Peña, Jimmy Stehberg and Mauricio A. Retamal
Biomolecules 2023, 13(3), 411; https://doi.org/10.3390/biom13030411 - 22 Feb 2023
Viewed by 1959
Abstract
Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived [...] Read more.
Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived from aminoglycosides have been developed as inhibitors of Cxs hemichannels. However, these studies have been performed in E. coli, which is a very simple model. Therefore, our main goal is to test whether these molecules have similar effects in mammalian cells. Methods: We transfected HeLa cells with the human Cx46tGFP and characterized the effect of a kanamycin-derived molecule (KI04) on Cx46 hemichannel activity by time-lapse recordings, changes in phosphorylation by Western blot, localization by epifluorescence, and possible binding sites by molecular dynamics (MD). Results: We observed that kanamycin and KI04 were the most potent inhibitors of Cx46 hemichannels among several aminoglycosides, presenting an IC50 close to 10 μM. The inhibitory effect was not associated with changes in Cx46 electrophoretic mobility or its intracellular localization. Interestingly, 5 mM DTT did not reverse KI04 inhibition, but the KI04 effect completely disappeared after washing out KI04 from the recording media. MD analysis revealed two putative binding sites of KI04 in the Cx46 hemichannel. Results: These results demonstrate that KI04 could be used as a Cx46 inhibitor and could help to develop future selective Cx46 inhibitors. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease)
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Review

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15 pages, 1692 KiB  
Review
Extrinsic and Intrinsic Factors Determine Expression Levels of Gap Junction-Forming Connexins in the Mammalian Retina
by Tamás Kovács-Öller, Gergely Szarka, Gyula Hoffmann, Loretta Péntek, Gréta Valentin, Liliana Ross and Béla Völgyi
Biomolecules 2023, 13(7), 1119; https://doi.org/10.3390/biom13071119 - 13 Jul 2023
Viewed by 2043
Abstract
Gap junctions (GJs) are not static bridges; instead, GJs as well as the molecular building block connexin (Cx) proteins undergo major expression changes in the degenerating retinal tissue. Various progressive diseases, including retinitis pigmentosa, glaucoma, age-related retinal degeneration, etc., affect neurons of the [...] Read more.
Gap junctions (GJs) are not static bridges; instead, GJs as well as the molecular building block connexin (Cx) proteins undergo major expression changes in the degenerating retinal tissue. Various progressive diseases, including retinitis pigmentosa, glaucoma, age-related retinal degeneration, etc., affect neurons of the retina and thus their neuronal connections endure irreversible changes as well. Although Cx expression changes might be the hallmarks of tissue deterioration, GJs are not static bridges and as such they undergo adaptive changes even in healthy tissue to respond to the ever-changing environment. It is, therefore, imperative to determine these latter adaptive changes in GJ functionality as well as in their morphology and Cx makeup to identify and distinguish them from alterations following tissue deterioration. In this review, we summarize GJ alterations that take place in healthy retinal tissue and occur on three different time scales: throughout the entire lifespan, during daily changes and as a result of quick changes of light adaptation. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease)
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27 pages, 2361 KiB  
Review
Gap Junctions and Connexins in Microglia-Related Oxidative Stress and Neuroinflammation: Perspectives for Drug Discovery
by Giuseppe Caruso, Lucia Di Pietro and Filippo Caraci
Biomolecules 2023, 13(3), 505; https://doi.org/10.3390/biom13030505 - 9 Mar 2023
Cited by 13 | Viewed by 3038
Abstract
Microglia represent the immune system of the brain. Their role is central in two phenomena, neuroinflammation and oxidative stress, which are at the roots of different pathologies related to the central nervous system (CNS). In order to maintain the homeostasis of the brain [...] Read more.
Microglia represent the immune system of the brain. Their role is central in two phenomena, neuroinflammation and oxidative stress, which are at the roots of different pathologies related to the central nervous system (CNS). In order to maintain the homeostasis of the brain and re-establish the equilibrium after a threatening imbalance, microglia communicate with each other and other cells within the CNS by receiving specific signals through membrane-bound receptors and then releasing neurotrophic factors into either the extracellular milieu or directly into the cytoplasm of nearby cells, such as astrocytes and neurons. These last two mechanisms rely on the activity of protein structures that enable the formation of channels in the membrane, namely, connexins and pannexins, that group and form gap junctions, hemichannels, and pannexons. These channels allow the release of gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, together with calcium ion (Ca2+), that seem to play a pivotal role in inter-cellular communication. The aim of the present review is focused on the physiology of channel protein complexes and their contribution to neuroinflammatory and oxidative stress-related phenomena, which play a central role in neurodegenerative disorders. We will then discuss how pharmacological modulation of these channels can impact neuroinflammatory phenomena and hypothesize that currently available nutraceuticals, such as carnosine and N-acetylcysteine, can modulate the activity of connexins and pannexins in microglial cells and reduce oxidative stress in neurodegenerative disorders. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease)
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17 pages, 11934 KiB  
Review
Hypertension Induces Pro-arrhythmic Cardiac Connexome Disorders: Protective Effects of Treatment
by Matus Sykora, Katarina Andelova, Barbara Szeiffova Bacova, Tamara Egan Benova, Adriana Martiskova, Vladimir Knezl and Narcis Tribulova
Biomolecules 2023, 13(2), 330; https://doi.org/10.3390/biom13020330 - 9 Feb 2023
Cited by 2 | Viewed by 2352
Abstract
Prolonged population aging and unhealthy lifestyles contribute to the progressive prevalence of arterial hypertension. This is accompanied by low-grade inflammation and over time results in heart dysfunction and failure. Hypertension-induced myocardial structural and ion channel remodeling facilitates the development of both atrial and [...] Read more.
Prolonged population aging and unhealthy lifestyles contribute to the progressive prevalence of arterial hypertension. This is accompanied by low-grade inflammation and over time results in heart dysfunction and failure. Hypertension-induced myocardial structural and ion channel remodeling facilitates the development of both atrial and ventricular fibrillation, and these increase the risk of stroke and sudden death. Herein, we elucidate hypertension-induced impairment of “connexome” cardiomyocyte junctions. This complex ensures cell-to-cell adhesion and coupling for electrical and molecular signal propagation. Connexome dysfunction can be a key factor in promoting the occurrence of both cardiac arrhythmias and heart failure. However, the available literature indicates that arterial hypertension treatment can hamper myocardial structural remodeling, hypertrophy and/or fibrosis, and preserve connexome function. This suggests the pleiotropic effects of antihypertensive agents, including anti-inflammatory. Therefore, further research is required to identify specific molecular targets and pathways that will protect connexomes, and it is also necessary to develop new approaches to maintain heart function in patients suffering from primary or pulmonary arterial hypertension. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease)
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