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Seeing Is Believing: Gap Junctions in Motion

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Xinbo Li

Biology 2021, 10(6), 494; https://doi.org/10.3390/biology10060494 - 02 Jun 2021

Cited by 2 | Viewed by 2104

Abstract

Gap junctional intercellular communication (GJIC) channels between cells are composed of connexin proteins that form hexamers (connexons) in adjacent plasma membranes [...] Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessArticle

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

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Biology 2023, 12(3), 346; https://doi.org/10.3390/biology12030346 - 21 Feb 2023

Viewed by 875

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessArticle

Maternal Adipocyte Connexin43 Gap Junctions Affect Breastmilk Lactose Levels and Neonate Growth in Mice

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Biology 2022, 11(7), 1023; https://doi.org/10.3390/biology11071023 - 07 Jul 2022

Viewed by 946

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessArticle

Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations

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Elvis Twumasi Aboagye

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Biology 2022, 11(3), 476; https://doi.org/10.3390/biology11030476 - 21 Mar 2022

Cited by 5 | Viewed by 2238

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessArticle

First Responders to Hyperosmotic Stress in Murine Astrocytes: Connexin 43 Gap Junctions Are Subject to an Immediate Ultrastructural Reorganization

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Biology 2021, 10(12), 1307; https://doi.org/10.3390/biology10121307 - 09 Dec 2021

Viewed by 1568

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessArticle

Extensive GJD2 Expression in the Song Motor Pathway Reveals the Extent of Electrical Synapses in the Songbird Brain

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Pepe Alcami

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Santhosh Totagera

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Nina Sohnius-Wilhelmi

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Stefan Leitner

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Benedikt Grothe

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Carolina Frankl-Vilches

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Manfred Gahr

Biology 2021, 10(11), 1099; https://doi.org/10.3390/biology10111099 - 25 Oct 2021

Viewed by 1950

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Review

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Open AccessReview

Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

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Biology 2023, 12(4), 505; https://doi.org/10.3390/biology12040505 - 27 Mar 2023

Viewed by 865

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintenance

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Olga M. Kutova

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Anton D. Pospelov

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Irina V. Balalaeva

Biology 2023, 12(2), 204; https://doi.org/10.3390/biology12020204 - 28 Jan 2023

Viewed by 1034

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions

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Yu-Han Guo

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Yi-Qing Yang

Biology 2022, 11(4), 489; https://doi.org/10.3390/biology11040489 - 23 Mar 2022

Cited by 4 | Viewed by 1629

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology

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Yi Zhu

Biology 2022, 11(2), 283; https://doi.org/10.3390/biology11020283 - 11 Feb 2022

Cited by 6 | Viewed by 2112

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

The Role of Connexin Hemichannels in Inflammatory Diseases

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Biology 2022, 11(2), 237; https://doi.org/10.3390/biology11020237 - 02 Feb 2022

Cited by 14 | Viewed by 1862

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

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Sebastian Curti

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Federico Davoine

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Antonella Dapino

Biology 2022, 11(1), 81; https://doi.org/10.3390/biology11010081 - 05 Jan 2022

Cited by 5 | Viewed by 1802

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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Open AccessReview

Gap Junctions and Hemichannels Composed of Connexins and Pannexins Mediate the Secondary Brain Injury Following Intracerebral Hemorrhage

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Biology 2022, 11(1), 27; https://doi.org/10.3390/biology11010027 - 25 Dec 2021

Cited by 12 | Viewed by 2405

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

(This article belongs to the Special Issue Gap Junctions and Connexins in Physiology, Pharmacology and Disease)

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