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Gap Junctions and Connexins in Physiology, Pharmacology and Disease
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Gap Junctions and Connexins in Physiology, Pharmacology and Disease

A topical collection in Biology (ISSN 2079-7737). This collection belongs to the section "Biochemistry and Molecular Biology".

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Editors

Dr. Yi Zhu

E-Mail Website
Collection Editor
Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
Interests: intercellular communication; adipocyte, gap junction; energy metabolism; mitochondria; FGF21; hyaluronan; extracellular matrix; glycocalyx
Dr. Sebastian Curti

E-Mail Website
Collection Editor
Laboratorio de Neurofisiología Celular, Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
Interests: electrophysiology; patch-clamp electrophysiology; synapses; neurophysiology; neurobiology
Dr. Xinbo Li

E-Mail
Collection Editor
Casey Eye Institute, Oregon Health and Science University, Portland, OR 97239, USA
Interests: connexin 36; electrical synapses; tight junctions; gap junctions; connexins; PDZ domains; Rodentia; oligodendroglia
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

A characteristic feature of many cell types that make up the human body, is their extensive connection by gap junctions, which consist of a family of 21 highly heterogeneously expressed connexin (genes) proteins that form membrane channels allowing direct cell-to-cell exchange of water, amino acids, nucleotides, ATP, calcium, cAMP, IP3, and other small molecules with molecular weight less than 1,000 dalton. Gap junctions play pivotal roles for cell differentiation, proliferation, homeostasis, electrical synaptic transmission and whole organ function. Connexins can form gap junction channels as well as hemichannels, recently, emerging evidence also demonstrated that connexins can have gap junction channel-independent function.

Gap junction family, which includes connexins, pannexins and innexins in invertebrates. Due to the highly conserved sequence in mouse orthologs of their corresponding human connexins, gene knockout mice have been used to define the functions of connexin genes, and importantly, many connexins global knockout mice are showing a lethal phenotype, indicating the functional importance of gap junctions in maintaining the homeostasis of cells and tissues. Mutations in connexin genes have been associated with a variety of human disease conditions. For example, Cx26 gene mutations have been identified as the most prevalent cause of congenital hearing loss in children. Therefore, some clinical tests in connexin gene mutations have been widely used in medical diagnosis.

To date, the revolutionary Cryo-EM has become a powerful tool in studying membrane proteins, and the 3-D structures of Cx26, Cx46 and Cx50 proteins have been resolved using Cryo-EM. From a structural point of view, the reconstruction of all the connexin transmembrane proteins will provide new clue for elucidation of the functions or binding sites of specific gap junction channel as well as hemichannel blockers.

In gap junction field, by utilizing the advanced techniques of molecular biology and biochemistry, new tools, including, but not limited to CRISPR-Cas9 genome editing, base editing, prime editing, Cre/loxP conditional knockout mice, optogenetics, siRNA, shRNA, nanoparticle mediated gene delivery system, modified safe and high efficacy viral vectors for gene therapy, peptide blockage and Cryo-EM, may open up new avenues for the development of therapeutics based on blockage or activation of gap junctions. In this Topical Collection, the roles of gap junctions in normal physiology, pharmacology and in the pathogenesis of several diseases will be presented.

Dr. Yi Zhu
Dr. Sebastian Curti
Dr. Xinbo Li
Collection Editors

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Keywords

  • gap junctions
  • connexins
  • pannexins
  • innexins
  • cell communication
  • cell–cell coupling
  • mutation

Published Papers (13 papers)

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2023

Jump to: 2022, 2021

19 pages, 3895 KiB  
Review
Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants
by Lu Mao, Yueqiang Wang, Lei An, Beiping Zeng, Yanyan Wang, Dmitrij Frishman, Mengli Liu, Yanyu Chen, Wenxue Tang and Hongen Xu
Biology 2023, 12(4), 505; https://doi.org/10.3390/biology12040505 - 27 Mar 2023
Cited by 7 | Viewed by 4003
Abstract
The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism [...] Read more.
The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the GJB2 missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible GJB2 missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated. Full article
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20 pages, 1891 KiB  
Article
Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias
by Yan-Jie Li, Juan Wang, Willy G. Ye, Xing-Yuan Liu, Li Li, Xing-Biao Qiu, Honghong Chen, Ying-Jia Xu, Yi-Qing Yang, Donglin Bai and Ri-Tai Huang
Biology 2023, 12(3), 346; https://doi.org/10.3390/biology12030346 - 21 Feb 2023
Cited by 7 | Viewed by 2632
Abstract
As the most prevalent type of birth malformation, congenital heart disease (CHD) gives rise to substantial mortality and morbidity as well as a socioeconomic burden. Although aggregating investigations highlight the genetic basis for CHD, the genetic determinants underpinning CHD remain largely obscure. In [...] Read more.
As the most prevalent type of birth malformation, congenital heart disease (CHD) gives rise to substantial mortality and morbidity as well as a socioeconomic burden. Although aggregating investigations highlight the genetic basis for CHD, the genetic determinants underpinning CHD remain largely obscure. In this research, a Chinese family suffering from autosomal dominant CHD (atrial septal defect) and arrhythmias was enrolled. A genome-wide genotyping with microsatellite markers followed by linkage assay as well as sequencing analysis was conducted. The functional effects of the discovered genetic mutation were characterized by dual patch-clamp electrophysiological recordings in N2A cells and propidium iodide uptake assays in HeLa cells. As a result, a novel genetic locus for CHD and arrhythmias was located on chromosome 17q21.31-q21.33, a 4.82-cM (5.12 Mb) region between two markers of D17S1861 and D17S1795. Sequencing assays of the genes at the mapped locus unveiled a novel heterozygous mutation in the GJC1 gene coding for connexin 45 (Cx45), NM_005497.4:c.550A>G;p.R184G, which was in co-segregation with the disease in the whole family and was not observed in 516 unrelated healthy individuals or gnomAD. Electrophysiological analyses revealed that the mutation significantly diminished the coupling conductance in homomeric cell pairs (R184G/R184G) and in cell pairs expressing either R184G/Cx45 or R184G/Cx43. Propidium iodide uptake experiments demonstrated that the Cx45 R184G mutation did not increase the Cx45 hemichannel function. This investigation locates a new genetic locus linked to CHD and arrhythmias on chromosome 17q21.31-q21.33 and indicates GJC1 as a novel gene predisposing to CHD and arrhythmias, implying clinical implications for prognostic risk assessment and personalized management of patients affected with CHD and arrhythmias. Full article
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27 pages, 1708 KiB  
Review
The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintenance
by Olga M. Kutova, Anton D. Pospelov and Irina V. Balalaeva
Biology 2023, 12(2), 204; https://doi.org/10.3390/biology12020204 - 28 Jan 2023
Cited by 12 | Viewed by 2725
Abstract
Today’s research on the processes of carcinogenesis and the vital activity of tumor tissues implies more attention be paid to constituents of the tumor microenvironment and their interactions. These interactions between cells in the tumor microenvironment can be mediated via different types of [...] Read more.
Today’s research on the processes of carcinogenesis and the vital activity of tumor tissues implies more attention be paid to constituents of the tumor microenvironment and their interactions. These interactions between cells in the tumor microenvironment can be mediated via different types of protein junctions. Connexins are one of the major contributors to intercellular communication. They form the gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc., between neighboring tumor cells as well as between tumor and stromal cells. Connexin hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, connexins have been reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. The pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization, and functionality as well as their channel assembly and non-channel functions. In this review, we have summarized the data on the contribution of connexins to the formation of the tumor microenvironment and to cancer initiation and progression. Full article
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2022

Jump to: 2023, 2021

10 pages, 1841 KiB  
Article
Maternal Adipocyte Connexin43 Gap Junctions Affect Breastmilk Lactose Levels and Neonate Growth in Mice
by Mingyang Huang, Anying Song, Xi Chen, Sarah Ishtiaq, Chunmei Wang, Darryl L. Hadsell, Qiong A. Wang and Yi Zhu
Biology 2022, 11(7), 1023; https://doi.org/10.3390/biology11071023 - 7 Jul 2022
Viewed by 1895
Abstract
Breastfeeding offers a broad spectrum of health benefits for infants. However, overnutrition and a steady increase in maternal obesity in the U.S. have made it harder for many mothers to produce and express breastmilk, and the quality of milk from obese mothers is [...] Read more.
Breastfeeding offers a broad spectrum of health benefits for infants. However, overnutrition and a steady increase in maternal obesity in the U.S. have made it harder for many mothers to produce and express breastmilk, and the quality of milk from obese mothers is also frequently compromised. Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological and functional change during lactation in mice. Lipid-filled adipocytes undergo lipolysis, and lipid droplets disappear to provide fatty acids and energy for breastmilk production. Once the animal stops lactation, these lipid-depleted adipocytes return as lipid-laden cells. This dynamic remodeling of the tissue is likely the result of active intercellular communications. Connexin43 (Cx43) is the most abundant connexin in the mammary adipose tissue that makes up the gap junctions for direct intercellular communications. Its expression is increased during lactation and reduced in obese mammary adipose tissue, which is resistant to lactation-induced remodeling. However, whether Cx43 is required for adipocyte remodeling and breastmilk production to support neonates’ growth has not been established. In this study, we used doxycycline-inducible adipocyte-specific Cx43-deleted mice and demonstrated that adipocyte Cx43 played a vital role in determining the carbohydrate levels in breastmilk, which may subsequently affect neonates’ growth. Full article
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15 pages, 1133 KiB  
Review
Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions
by Yu-Han Guo and Yi-Qing Yang
Biology 2022, 11(4), 489; https://doi.org/10.3390/biology11040489 - 23 Mar 2022
Cited by 15 | Viewed by 3380
Abstract
Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have [...] Read more.
Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF. Full article
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14 pages, 1822 KiB  
Article
Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations
by Elvis Twumasi Aboagye, Samuel Mawuli Adadey, Kevin Esoh, Mario Jonas, Carmen de Kock, Lucas Amenga-Etego, Gordon A. Awandare and Ambroise Wonkam
Biology 2022, 11(3), 476; https://doi.org/10.3390/biology11030476 - 21 Mar 2022
Cited by 6 | Viewed by 3430
Abstract
Gap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To [...] Read more.
Gap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To date, in the African continent, GJB2-p.(Arg143Trp) has only been reported in Ghana. Using whole-exome sequencing data from 32 individuals from 16 families segregating NSHI, and 38 unrelated hearing controls with the same ethnolinguistic background, we investigated the date and origin of p.(Arg143Trp) in Ghana using linked markers. With a Bayesian linkage disequilibrium gene mapping method, we estimated GJB2-p.(Arg143Trp) to have originated about 9625 years (385 generations) ago in Ghana. A haplotype analysis comparing data extracted from Ghanaians and those from the 1000 Genomes project revealed that GJB2-p.(Arg143Trp) is carried on different haplotype backgrounds in Ghanaian and Japanese populations, as well as among populations of European ancestry, lending further support to the multiple independent origins of the variant. In addition, we found substantial haplotype conservation in the genetic background of Ghanaian individuals with biallelic GJB2-p.(Arg143Trp) compared to the GJB2-p.(Arg143Trp)-negative group with normal hearing from Ghana, suggesting a strong evolutionary constraint in this genomic region in Ghanaian populations that are homozygous for GJB2-p.(Arg143Trp). The present study evaluates the age of GJB2-p.(Arg143Trp) at 9625 years and supports the multiple independent origins of this variant in the global population. Full article
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19 pages, 1023 KiB  
Review
Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology
by Yi Zhu
Biology 2022, 11(2), 283; https://doi.org/10.3390/biology11020283 - 11 Feb 2022
Cited by 16 | Viewed by 4822
Abstract
For the first time in animal evolution, the emergence of gap junctions allowed direct exchanges of cellular substances for communication between two cells. Innexin proteins constituted primordial gap junctions until the connexin protein emerged in deuterostomes and took over the gap junction function. [...] Read more.
For the first time in animal evolution, the emergence of gap junctions allowed direct exchanges of cellular substances for communication between two cells. Innexin proteins constituted primordial gap junctions until the connexin protein emerged in deuterostomes and took over the gap junction function. After hundreds of millions of years of gene duplication, the connexin gene family now comprises 21 members in the human genome. Notably, GJA1, which encodes the Connexin43 protein, is one of the most widely expressed and commonly studied connexin genes. The loss of Gja1 in mice leads to swelling and a blockage of the right ventricular outflow tract and death of the embryos at birth, suggesting a vital role of Connexin43 gap junction in heart development. Since then, the importance of Connexin43-mediated gap junction function has been constantly expanded to other types of cells. Other than forming gap junctions, Connexin43 can also form hemichannels to release or uptake small molecules from the environment or even mediate many physiological processes in a gap junction-independent manner on plasma membranes. Surprisingly, Connexin43 also localizes to mitochondria in the cell, playing important roles in mitochondrial potassium import and respiration. At the molecular level, Connexin43 mRNA and protein are processed with very distinct mechanisms to yield carboxyl-terminal fragments with different sizes, which have their unique subcellular localization and distinct biological activities. Due to many exciting advancements in Connexin43 research, this review aims to start with a brief introduction of Connexin43 and then focuses on updating our knowledge of its gap junction-independent functions. Full article
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20 pages, 812 KiB  
Review
The Role of Connexin Hemichannels in Inflammatory Diseases
by Bo Peng, Chengping Xu, Shuaiwei Wang, Yijie Zhang and Wei Li
Biology 2022, 11(2), 237; https://doi.org/10.3390/biology11020237 - 2 Feb 2022
Cited by 27 | Viewed by 3954
Abstract
The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels [...] Read more.
The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on the membranes of apposing cells. Non-junctional connexin hemichannels (CxHC) provide a conduit between the cell interior and the extracellular milieu, and are believed to be in a protectively closed state under physiological conditions. The development and characterization of the peptide mimetics of the amino acid sequences of connexins have resulted in the development of a panel of blockers with a higher selectivity for CxHC, which have become important tools for defining the role of CxHC in various biological processes. It is increasingly clear that CxHC can be induced to open by pathogen-associated molecular patterns. The opening of CxHC facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of CxHC leads to attenuated inflammation, reduced tissue injury and improved organ function in human and animal models of about thirty inflammatory diseases and disorders. These findings demonstrate that CxHC may contribute to the intensification of inflammation, and serve as a common target in the treatments of various inflammatory diseases. In this review, we provide an update on the progress in the understanding of CxHC, with a focus on the role of these channels in inflammatory diseases. Full article
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24 pages, 6556 KiB  
Review
Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms
by Sebastian Curti, Federico Davoine and Antonella Dapino
Biology 2022, 11(1), 81; https://doi.org/10.3390/biology11010081 - 5 Jan 2022
Cited by 10 | Viewed by 4446
Abstract
Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. Circuits of electrically coupled neurons are widespread in these animals. Plus, [...] Read more.
Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. Circuits of electrically coupled neurons are widespread in these animals. Plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations such as lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on the gap junction resistance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage and ligand gated channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here, we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function. Full article
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2021

Jump to: 2023, 2022

11 pages, 1412 KiB  
Review
Gap Junctions and Hemichannels Composed of Connexins and Pannexins Mediate the Secondary Brain Injury Following Intracerebral Hemorrhage
by Yan Zhang, Suliman Khan, Yang Liu, Rabeea Siddique, Ruiyi Zhang, Voon Wee Yong and Mengzhou Xue
Biology 2022, 11(1), 27; https://doi.org/10.3390/biology11010027 - 25 Dec 2021
Cited by 24 | Viewed by 4171
Abstract
Intracerebral hemorrhage (ICH) is a devastating disease with high mortality and morbidity; the mortality rate ranges from 40% at 1 month to 54% at 1 year; only 12–39% achieve good outcomes and functional independence. ICH affects nearly 2 million patients worldwide annually. In [...] Read more.
Intracerebral hemorrhage (ICH) is a devastating disease with high mortality and morbidity; the mortality rate ranges from 40% at 1 month to 54% at 1 year; only 12–39% achieve good outcomes and functional independence. ICH affects nearly 2 million patients worldwide annually. In ICH development, the blood leakage from ruptured vessels generates sequelae of secondary brain injury (SBI). This mechanism involves activated astrocytes and microglia, generation of reactive oxygen species (ROS), the release of reactive nitrogen species (RNS), and disrupted blood brain barrier (BBB). In addition, inflammatory cytokines and chemokines, heme compounds, and products of hematoma are accumulated in the extracellular spaces, thereby resulting in the death of brain cells. Recent evidence indicates that connexins regulate microglial activation and their phenotypic transformation. Moreover, communications between neurons and glia via gap junctions have crucial roles in neuroinflammation and cell death. A growing body of evidence suggests that, in addition to gap junctions, hemichannels (composed of connexins and pannexins) play a key role in ICH pathogenesis. However, the precise connection between connexin and pannexin channels and ICH remains to be resolved. This review discusses the pathological roles of gap junctions and hemichannels in SBI following ICH, with the intent of discovering effective therapeutic options of strategies to treat ICH. Full article
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17 pages, 4179 KiB  
Article
First Responders to Hyperosmotic Stress in Murine Astrocytes: Connexin 43 Gap Junctions Are Subject to an Immediate Ultrastructural Reorganization
by Anja Beckmann, Johanna Recktenwald, Alice Ferdinand, Alexander Grißmer and Carola Meier
Biology 2021, 10(12), 1307; https://doi.org/10.3390/biology10121307 - 9 Dec 2021
Viewed by 2574
Abstract
In a short-term model of hyperosmotic stress, primary murine astrocytes were stimulated with a hyperosmolar sucrose solution for five minutes. Astrocytic gap junctions, which are mainly composed of Connexin (Cx) 43, displayed immediate ultrastructural changes, demonstrated by freeze–fracture replica immunogold labeling: their area, [...] Read more.
In a short-term model of hyperosmotic stress, primary murine astrocytes were stimulated with a hyperosmolar sucrose solution for five minutes. Astrocytic gap junctions, which are mainly composed of Connexin (Cx) 43, displayed immediate ultrastructural changes, demonstrated by freeze–fracture replica immunogold labeling: their area, perimeter, and distance of intramembrane particles increased, whereas particle numbers per area decreased. Ultrastructural changes were, however, not accompanied by changes in Cx43 mRNA expression. In contrast, transcription of the gap junction regulator zonula occludens (ZO) protein 1 significantly increased, whereas its protein expression was unaffected. Phosphorylation of Serine (S) 368 of the Cx43 C–terminus has previously been associated with gap junction disassembly and reduction in gap junction communication. Hyperosmolar sucrose treatment led to enhanced phosphorylation of Cx43S368 and was accompanied by inhibition of gap junctional intercellular communication, demonstrated by a scrape loading-dye transfer assay. Taken together, Cx43 gap junctions are fast reacting elements in response to hyperosmolar challenges and can therefore be considered as one of the first responders to hyperosmolarity. In this process, phosphorylation of Cx43S368 was associated with disassembly of gap junctions and inhibition of their function. Thus, modulation of the gap junction assembly might represent a target in the treatment of brain edema or trauma. Full article
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Graphical abstract

16 pages, 5721 KiB  
Article
Extensive GJD2 Expression in the Song Motor Pathway Reveals the Extent of Electrical Synapses in the Songbird Brain
by Pepe Alcami, Santhosh Totagera, Nina Sohnius-Wilhelmi, Stefan Leitner, Benedikt Grothe, Carolina Frankl-Vilches and Manfred Gahr
Biology 2021, 10(11), 1099; https://doi.org/10.3390/biology10111099 - 25 Oct 2021
Cited by 1 | Viewed by 3637
Abstract
Birdsong is a precisely timed animal behavior. The connectivity of song premotor neural networks has been proposed to underlie the temporal patterns of neuronal activity that control vocal muscle movements during singing. Although the connectivity of premotor nuclei via chemical synapses has been [...] Read more.
Birdsong is a precisely timed animal behavior. The connectivity of song premotor neural networks has been proposed to underlie the temporal patterns of neuronal activity that control vocal muscle movements during singing. Although the connectivity of premotor nuclei via chemical synapses has been characterized, electrical synapses and their molecular identity remain unexplored. We show with in situ hybridizations that GJD2 mRNA, coding for the major channel-forming electrical synapse protein in mammals, connexin 36, is expressed in the two nuclei that control song production, HVC and RA from canaries and zebra finches. In canaries’ HVC, GJD2 mRNA is extensively expressed in GABAergic and only a fraction of glutamatergic cells. By contrast, in RA, GJD2 mRNA expression is widespread in glutamatergic and GABAergic neurons. Remarkably, GJD2 expression is similar in song nuclei and their respective embedding brain regions, revealing the widespread expression of GJD2 in the avian brain. Inspection of a single-cell sequencing database from zebra and Bengalese finches generalizes the distributions of electrical synapses across cell types and song nuclei that we found in HVC and RA from canaries, reveals a differential GJD2 mRNA expression in HVC glutamatergic subtypes and its transient increase along the neurogenic lineage. We propose that songbirds are a suitable model to investigate the contribution of electrical synapses to motor skill learning and production. Full article
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3 pages, 177 KiB  
Editorial
Seeing Is Believing: Gap Junctions in Motion
by Xinbo Li
Biology 2021, 10(6), 494; https://doi.org/10.3390/biology10060494 - 2 Jun 2021
Cited by 3 | Viewed by 2877
Abstract
Gap junctional intercellular communication (GJIC) channels between cells are composed of connexin proteins that form hexamers (connexons) in adjacent plasma membranes [...] Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Post-translational Modifications and Multi-site Control of Connexin43
Authors: Corbin Glufka; Jeffery Li; Vincent Chen
Affiliation: Department of Chemistry, Brandon University, Room 4-11, John R. Brodie Science Centre， 270 18th Street, Brandon, Manitoba, Canada
Abstract: Post-translational modifications (PTMs) are dynamic chemical events that control and fine tune the function of a cell. Occurring at any point within the life cycle of a protein, the presence or absence of a PTMs can profoundly influence gene function and thus regulatory events underlying health and disease. The identification binary and combinatorial PTMs such as phosphorylation are of wide interest to the gap junction field. In this review we will discuss the current state of knowledge of multi-site PTMs and how these modifications maybe accessed to help determine their effects on connexin structure, function, and gap junctional intercellular communication.

Title: Connexin36 interacting proteins
Authors: Xinbo Li1; Rongqiang Li2
Affiliation: 1. Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA 2. Department of Urology, Weihaiwei hospital, Weihai, Shandong, China
Abstract: It is well established that gap junction protein connexin36 (Cx36) is one of the major components of the morphological structure of electrical synapses in the central nervous system. Recent emerging evidence indicating that Cx36 contains a highly conserved C-terminus SAYV PDZ domain binding motif, and the SAYV PDZ domain binding motif is required for the interaction of Cx36 with a variety of PDZ domain containing proteins. In this review, we will summarize the current progress in studying Cx36 associated proteins, including our recently discovered the Rho-guanine nucleotide exchange factor PDZ-RhoGEF, and their functional and regulatory roles in the formation of electrical synapses comprised of Cx36.

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