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Developmental Neurobiology May 2017Methods such as electron microscopy and electrophysiology led to the understanding that gap junctions were dense arrays of channels connecting the intracellular... (Comparative Study)
Comparative Study Review
Methods such as electron microscopy and electrophysiology led to the understanding that gap junctions were dense arrays of channels connecting the intracellular environments within almost all animal tissues. The characteristics of gap junctions were remarkably similar in preparations from phylogenetically diverse animals such as cnidarians and chordates. Although few studies directly compared them, minor differences were noted between gap junctions of vertebrates and invertebrates. For instance, a slightly wider gap was noted between cells of invertebrates and the spacing between invertebrate channels was generally greater. Connexins were identified as the structural component of vertebrate junctions in the 1980s and innexins as the structural component of pre-chordate junctions in the 1990s. Despite a lack of similarity in gene sequence, connexins and innexins are remarkably similar. Innexins and connexins have the same membrane topology and form intercellular channels that play a variety of tissue- and temporally specific roles. Both protein types oligomerize to form large aqueous channels that allow the passage of ions and small metabolites and are regulated by factors such as pH, calcium, and voltage. Much more is currently known about the structure, function, and structure-function relationships of connexins. However, the innexin field is expanding. Greater knowledge of innexin channels will permit more detailed comparisons with their connexin-based counterparts, and provide insight into the ubiquitous yet specific roles of gap junctions. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 522-547, 2017.
Topics: Animals; Connexins; Gap Junctions; Ion Channels
PubMed: 27582044
DOI: 10.1002/dneu.22447 -
FEBS Letters Apr 2014Connexins, a family of transmembrane proteins, are components of both gap junction channels and hemichannels, which mediate the exchange of ions and small molecules... (Review)
Review
Connexins, a family of transmembrane proteins, are components of both gap junction channels and hemichannels, which mediate the exchange of ions and small molecules between adjacent cells, and between the inside and outside of the cell, respectively. Substantial advancements have been made in the comprehension of the role of gap junctions and hemichannels in coordinating cellular events. In recent years, a plethora of studies demonstrate a role of connexin proteins in the regulation of tissue homeostasis that occurs independently of their channel activities. This is shown in the context of cell growth, adhesion, migration, apoptosis, and signaling. The major mechanisms of these channel-independent activities still remain to be discovered. In this review, we provide an updated overview on the current knowledge of gap junction- and hemichannel-independent functions of connexins, in particular, their effects on tumorigenesis, neurogenesis and disease development.
Topics: Animals; Apoptosis; Cell Cycle; Cell Movement; Connexins; Gap Junctions; Humans; Signal Transduction
PubMed: 24434539
DOI: 10.1016/j.febslet.2014.01.001 -
Cellular and Molecular Life Sciences :... Feb 2020Gap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junctions have a wide... (Review)
Review
Gap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junctions have a wide diversity of physiological functions, playing critical roles in both excitable and non-excitable tissues. Gap junction channels are formed by integral membrane proteins called connexins. Inherited or acquired alterations in connexins are associated with numerous diseases, including heart failure, neuropathologies, deafness, skin disorders, cataracts and cancer. Gap junctions are highly dynamic structures and by modulating the turnover rate of connexins, cells can rapidly alter the number of gap junction channels at the plasma membrane in response to extracellular or intracellular cues. Increasing evidence suggests that ubiquitination has important roles in the regulation of endoplasmic reticulum-associated degradation of connexins as well as in the modulation of gap junction endocytosis and post-endocytic sorting of connexins to lysosomes. In recent years, researchers have also started to provide insights into the physiological roles of connexin ubiquitination in specific tissue types. This review provides an overview of the advances made in understanding the roles of connexin ubiquitination in the regulation of gap junction intercellular communication and discusses the emerging physiological and pathophysiological implications of these processes.
Topics: Animals; Cataract; Cell Communication; Connexin 43; Connexins; Gap Junctions; Heart Diseases; Humans; Neoplasms; Protein Processing, Post-Translational; Ubiquitination
PubMed: 31501970
DOI: 10.1007/s00018-019-03285-0 -
Biochimica Et Biophysica Acta.... Jan 2018Connexins are chordate gap junction channel proteins that, by enabling direct communication between the cytosols of adjacent cells, create a unique cell signalling... (Review)
Review
Connexins are chordate gap junction channel proteins that, by enabling direct communication between the cytosols of adjacent cells, create a unique cell signalling network. Gap junctional intercellular communication (GJIC) has important roles in controlling cell growth and differentiation and in tissue development and homeostasis. Moreover, several non-canonical connexin functions unrelated to GJIC have been discovered. Of the 21 members of the human connexin family, connexin 43 (Cx43) is the most widely expressed and studied. The long cytosolic C-terminus (CT) of Cx43 is subject to extensive post-translational modifications that modulate its intracellular trafficking and gap junction channel gating. Moreover, the Cx43 CT contains multiple domains involved in protein interactions that permit crosstalk between Cx43 and cytoskeletal and regulatory proteins. These domains endow Cx43 with the capacity to affect cell growth and differentiation independently of GJIC. Here, we review the current understanding of the regulation and unique functions of the Cx43 CT, both as an essential component of full-length Cx43 and as an independent signalling hub. We highlight the complex regulatory and signalling networks controlled by the Cx43 CT, including the extensive protein interactome that underlies both gap junction channel-dependent and -independent functions. We discuss these data in relation to the recent discovery of the direct translation of specific truncated forms of Cx43. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
Topics: Animals; Connexin 43; Cytoskeleton; Gap Junctions; Humans; Ion Channel Gating; Ion Channels; Protein Domains; Protein Processing, Post-Translational; Protein Transport; Structure-Activity Relationship
PubMed: 28526583
DOI: 10.1016/j.bbamem.2017.05.008 -
FEBS Letters Apr 2014Connexin proteins are short-lived within the cell, whether present in the secretory pathway or in gap junction plaques. Their levels can be modulated by their rate of... (Review)
Review
Connexin proteins are short-lived within the cell, whether present in the secretory pathway or in gap junction plaques. Their levels can be modulated by their rate of degradation. Connexins, at different stages of assembly, are degraded through the proteasomal, endo-/lysosomal, and phago-/lysosomal pathways. In this review, we summarize the current knowledge about connexin and gap junction degradation including the signals and protein-protein interactions that participate in their targeting for degradation.
Topics: Animals; Connexins; Endosomes; Gap Junctions; Humans; Lysosomes; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination
PubMed: 24486527
DOI: 10.1016/j.febslet.2014.01.031 -
Molecular Biology of the Cell Oct 2021Gap junctions mediate direct cell-to-cell communication by forming channels that physically couple cells, thereby linking their cytoplasm, permitting the exchange of...
Gap junctions mediate direct cell-to-cell communication by forming channels that physically couple cells, thereby linking their cytoplasm, permitting the exchange of molecules, ions, and electrical impulses. Gap junctions are assembled from connexin (Cx) proteins, with connexin 43 (Cx43) being the most ubiquitously expressed and best studied. While the molecular events that dictate the Cx43 life cycle have largely been characterized, the unusually short half-life of Cxs of only 1-5 h, resulting in constant endocytosis and biosynthetic replacement of gap junction channels, has remained puzzling. The Cx43 C-terminal (CT) domain serves as the regulatory hub of the protein affecting all aspects of gap junction function. Here, deletion within the Cx43 CT (amino acids 256-289), a region known to encode key residues regulating gap junction turnover, is employed to examine the effects of dysregulated Cx43 gap junction endocytosis using cultured cells (Cx43) and a zebrafish model (). We report that this CT deletion causes defective gap junction endocytosis as well as increased gap junction intercellular communication. Increased Cx43 protein content in cx zebrafish, specifically in the cardiac tissue, larger gap junction plaques, and longer Cx43 protein half-lives coincide with severely impaired development. Our findings demonstrate for the first time that continuous Cx43 gap junction endocytosis is an essential aspect of gap junction function and, when impaired, gives rise to significant physiological problems as revealed here for cardiovascular development and function.
Topics: Animals; Cell Communication; Cell Line; Cells, Cultured; Connexins; Endocytosis; Gap Junctions; Membrane Proteins; Phosphorylation; Protein Domains; Protein Transport; Zebrafish; Zebrafish Proteins
PubMed: 34379446
DOI: 10.1091/mbc.E20-12-0797 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Nov 2015Gap junctions play a critical role in electrical synchronization and exchange of small molecules between neighboring cells; connexins are a family of structurally... (Review)
Review
Gap junctions play a critical role in electrical synchronization and exchange of small molecules between neighboring cells; connexins are a family of structurally related transmembrane proteins that assemble to form vertebrate gap junctions. Hyperglycemia changes the structure gap junction proteins and their expression, resulting in obstruction of neural regeneration, vascular function and wound healing, and also promoting vascular atherosclerosis. These pathogenic factors would cause diabetic foot ulcers. This article reviews the involvement of connexins in pathogenesis of diabetic foot.
Topics: Atherosclerosis; Connexins; Diabetic Foot; Gap Junctions; Humans; Hyperglycemia; Regeneration; Wound Healing
PubMed: 26822053
DOI: 10.3785/j.issn.1008-9292.2015.11.14 -
Journal of Neuroscience Research Jan 2018In the central nervous system (CNS), connexin (Cx)s and pannexin (Panx)s are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal... (Review)
Review
In the central nervous system (CNS), connexin (Cx)s and pannexin (Panx)s are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal Cx gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, glial gap junctions help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca slow wave propagation. Panxs do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission, alongside Cx hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in excessive neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how the disruption of gap junctions and hemichannels lead to abnormal glutamatergic transmission, purinergic signaling, and seizures.
Topics: Animals; Calcium Signaling; Central Nervous System Diseases; Connexins; Gap Junctions; Homeostasis; Humans; Nerve Tissue Proteins; Neuroglia
PubMed: 28580666
DOI: 10.1002/jnr.24088 -
Cellular and Molecular Life Sciences :... Feb 2008Gap junctions (GJs) are composed of proteins that form a channel connecting the cytoplasm of adjacent cells. Connexins were initially considered to be the only proteins... (Review)
Review
Gap junctions (GJs) are composed of proteins that form a channel connecting the cytoplasm of adjacent cells. Connexins were initially considered to be the only proteins capable of GJ formation. Another family of GJ proteins (innexins) were first found in invertebrates and were proposed to be renamed pannexins after their orthologs were discovered in vertebrates. The lack of both connexins and pannexins in the genomes of some metazoans suggests that other, still undiscovered GJ proteins exist. In vertebrates, connexins and pannexins co-exist. Here we discuss whether vertebrate pannexins have a nonredundant role in animal physiology. Pannexin channels appear to be suited for ATP and calcium signaling and play a role in the maintenance of calcium homeostasis by mechanisms implicating both GJ and nonjunctional function. Suggested roles in the ischemic death of neurons, schizophrenia, inflammation and tumor suppression have drawn much attention to exploring the molecular properties and cellular functions of pannexins.
Topics: Animals; Calcium Signaling; Cell Communication; Connexins; Gap Junctions; Humans; Nerve Tissue Proteins; Nervous System Physiological Phenomena; Paracrine Communication; Phylogeny; Taste
PubMed: 17982731
DOI: 10.1007/s00018-007-7200-1 -
Biomolecules Nov 2020The 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...
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.
Topics: Animals; Cell Line; Connexin 43; Gap Junctions; Phosphorylation; Rats; src-Family Kinases
PubMed: 33255329
DOI: 10.3390/biom10121596