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BBA - Biomembranes (v.1828, #1)
Evolutionary analyses of gap junction protein families by Federico Abascal; Rafael Zardoya (pp. 4-14).
Gap junctions are intercellular channels that link the cytoplasm of neighboring cells in animals, enabling straight passage of ions and small molecules. Two different protein families, pannexins and connexins, form these channels. Pannexins are present in all eumetazoans but echinoderms (and are termed innexins in non-chordates) whereas connexins are exclusive of chordates. Despite little sequence similarity, both types of proteins assemble into a common secondary structure with four hydrophobic transmembrane domains linked by one cytoplasmic and two extracellular loops. Although all pannexins and connexins are packed into hexamers forming single channels, only non-chordate pannexins (innexins) and connexins form gap junctions. Here, we revisit and review evolutionary features of pannexin and connexin protein families. For that, we retrieved members of both families from several complete genome projects, and searched for conserved positions in the independent alignments of pannexin and connexin protein families. In addition, the degree of evolutionary conservation was mapped onto the 3D structure of a connexon (i.e. the assembly of six connexins). Finally, we reconstructed independent phylogenies of pannexins and connexins using probabilistic methods of inference. Non-chordate ( Drosophila and Caenorhabditis) pannexins (i.e. innexins) were recovered as sister group of chordate pannexins, which included Ciona paralogs and vertebrate pannexins (pannexin-1 and pannexin-3 were recovered as sister groups to the exclusion of pannexin-2). In the reconstructed phylogeny of connexins, subfamilies α and β were recovered as sister groups to the exclusion of subfamily γ, whereas δ and (the newly identified) ζ subfamilies were recovered at the base of the tree. A sixth highly divergent subfamily (ε) was not included in the phylogenetic analyses. Several groups of paralogy were identified within each subfamily. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► We retrieved pannexins and connexins from several complete genome projects. ► We searched for conserved positions in pannexin and connexin independent alignments. ► We mapped evolutionary conservation onto the 3D structure of a connexon. ► Non-chordate pannexins are sister group of Ciona and vertebrate pannexin paralogs. ► The phylogeny of chordate connexins reveals five subfamilies with many paralogs.
Keywords: Connexin; Innexin; Pannexin; Molecular phylogeny; Maximum likelihood; Bayesian inference
The biochemistry and function of pannexin channels by Silvia Penuela; Ruchi Gehi; Dale W. Laird (pp. 15-22).
Three family members compose the pannexin family of channel-forming glycoproteins (Panx1, Panx2 and Panx3). Their primary function is defined by their capacity to form single-membrane channels that are regulated by post-translational modifications, channel intermixing, and sub-cellular expression profiles. Panx1 is ubiquitously expressed in many mammalian tissues, while Panx2 and Panx3 appear to be more restricted in their expression. Paracrine functions of Panx1 as an ATP release channel have been extensively studied and this channel plays a key role, among others, in the release of “find-me” signals for apoptotic cell clearance. In addition Panx1 has been linked to propagation of calcium waves, regulation of vascular tone, mucociliary lung clearance, taste-bud function and has been shown to act like a tumor suppressor in gliomas. Panx1 channel opening can also be detrimental, contributing to cell death and seizures under ischemic or epileptic conditions and even facilitating HIV-1 viral infection. Panx2 is involved in differentiation of neurons while Panx3 plays a role in the differentiation of chondrocytes, osteoblasts and the maturation and transport of sperm. Using the available Panx1 knockout mouse models it has now become possible to explore some of its physiological functions. However, given the potential for one pannexin to compensate for another it seems imperative to generate single and double knockout mouse models involving all three pannexins and evaluate their interplay in normal differentiation and development as well as in malignant transformation and disease. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.► Pannexins are glycoproteins that form functional single membrane channels. ► ATP-release via Panx1 is involved in normal physiological functions and disease states. ► Panx2 regulates differentiation in neurons and can be palmitoylated. ► Panx3 plays a role in development of skin, bone, sperm and cartilage. ► Four Panx1-KO mice have been developed to study its role in lung, brain, and immune system.
Keywords: Pannexin; Biochemistry; Physiological function; Panx1; Panx2; Panx3
Connexin multi-site phosphorylation: Mass spectrometry-based proteomics fills the gap by Vincent C. Chen; Joost W. Gouw; Christian C. Naus; Leonard J. Foster (pp. 23-34).
Connexins require an integrated network for protein synthesis, assembly, gating, internalization, degradation and feedback control that are necessary to regulate the biosynthesis, and turnover of gap junction channels. At the most fundamental level, the introduction of sequence-altering, modifications introduces changes in protein conformation, activity, charge, stability and localization. Understanding the sites, patterns and magnitude of protein post-translational modification, including phosphorylation, is absolutely critical. Historically, the examination of connexin phosphorylation has been placed within the context that one or small number of sites of modification strictly corresponds to one molecular function. However, the release of high-profile proteomic datasets appears to challenge this dogma by demonstrating connexins undergo multiple levels of multi-site phosphorylation. With the growing prominence of mass spectrometry in biology and medicine, we are now getting a glimpse of the richness of connexin phosphate signals. Having implications to health and disease, this review provides an overview of technologies in the context of targeted and discovery proteomics, and further discusses how these techniques are being applied to “fill the gaps” in understanding of connexin post-translational control. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► We provide an up to date overview of mass spectrometry (MS)-based proteomics. ► Cx43 appears to undergo multiple levels of multisite phosphorylation. ► Bioinformatics reveal the majority of sites are consensus to multiple kinases. ► Multisite phosphorylation sequence and order provides insight into the Cx code.
Keywords: Connexin; Cx43; Gap junction; J; Phosphorylation; Proteomic; Multisite phosphorylation
Paracrine signaling through plasma membrane hemichannels by Nan Wang; Marijke De Bock; Elke Decrock; Mélissa Bol; Ashish Gadicherla; Mathieu Vinken; Vera Rogiers; Feliksas F. Bukauskas; Geert Bultynck; Luc Leybaert (pp. 35-50).
Plasma membrane hemichannels composed of connexin (Cx) proteins are essential components of gap junction channels but accumulating evidence suggests functions of hemichannels beyond the communication provided by junctional channels. Hemichannels not incorporated into gap junctions, called unapposed hemichannels, can open in response to a variety of signals, electrical and chemical, thereby forming a conduit between the cell's interior and the extracellular milieu. Open hemichannels allow the bidirectional passage of ions and small metabolic or signaling molecules of below 1–2kDa molecular weight. In addition to connexins, hemichannels can also be formed by pannexin (Panx) proteins and current evidence suggests that Cx26, Cx32, Cx36, Cx43 and Panx1, form hemichannels that allow the diffusive release of paracrine messengers. In particular, the case is strong for ATP but substantial evidence is also available for other messengers like glutamate and prostaglandins or metabolic substances like NAD+ or glutathione. While this field is clearly in expansion, evidence is still lacking at essential points of the paracrine signaling cascade that includes not only messenger release, but also downstream receptor signaling and consequent functional effects. The data available at this moment largely derives from in vitro experiments and still suffers from the difficulty of separating the functions of connexin-based hemichannels from gap junctions and from pannexin hemichannels. However, messengers like ATP or glutamate have universal roles in the body and further defining the contribution of hemichannels as a possible release pathway is expected to open novel avenues for better understanding their contribution to a variety of physiological and pathological processes. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Connexin and pannexin form unapposed hemichannels in the plasma membrane. ► Hemichannels are activated by a variety of (patho)physiological stimuli. ► Substances released via hemichannels participate in paracrine signaling cascade. ► Interplay of hemichannels with intercellular signaling opens a new pathway to coordinate cellular events.
Keywords: Connexin hemichannel; Pannexin hemichannel; Paracrine signaling
Structural basis for the selective permeability of channels made of communicating junction proteins by Jose F. Ek-Vitorin; Janis M. Burt (pp. 51-68).
The open state(s) of gap junction channels is evident from their permeation by small ions in response to an applied intercellular (transjunctional/transchannel) voltage gradient. That an open channel allows variable amounts of current to transit from cell-to-cell in the face of a constant intercellular voltage difference indicates channel open/closing can be complete or partial. The physiological significance of such open state options is, arguably, the main concern of junctional regulation. Because gap junctions are permeable to many substances, it is sensible to inquire whether and how each open state influences the intercellular diffusion of molecules as valuable as, but less readily detected than current-carrying ions. Presumably, structural changes perceived as shifts in channel conductivity would significantly alter the transjunctional diffusion of molecules whose limiting diameter approximates the pore's limiting diameter. Moreover, changes in junctional permeability to some molecules might occur without evident changes in conductivity, either at macroscopic or single channel level. Open gap junction channels allow the exchange of cytoplasmic permeants between contacting cells by simple diffusion. The identity of such permeants, and the functional circumstances and consequences of their junctional exchange presently constitute the most urgent (and demanding) themes of the field. Here, we consider the necessity for regulating this exchange, the possible mechanism(s) and structural elements likely involved in such regulation, and how regulatory phenomena could be perceived as changes in chemical vs. electrical coupling; an overall reflection on our collective knowledge of junctional communication is then applied to suggest new avenues of research. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Multiple connexin regions define permeability and selectivity of gap junctions. ► Gating, electrostatic interactions and phosphorylation modify channel function. ► Junctional molecular and ionic permeability may change in non-parallel fashion. ► Multiple mechanisms of channel gating have been proposed. ► Naturally existing junctional permeants are not broadly known.
Keywords: Permeability; Selectivity; Gap junction; Regulation; Synchronization
Gap junction communication in myelinating glia by Anna Nualart-Marti; Carles Solsona; R. Douglas Fields (pp. 69-78).
Gap junction communication is crucial for myelination and axonal survival in both the peripheral nervous system (PNS) and central nervous system (CNS). This review examines the different types of gap junctions in myelinating glia of the PNS and CNS (Schwann cells and oligodendrocytes respectively), including their functions and involvement in neurological disorders. Gap junctions mediate intercellular communication among Schwann cells in the PNS, and among oligodendrocytes and between oligodendrocytes and astrocytes in the CNS. Reflexive gap junctions mediating transfer between different regions of the same cell promote communication between cellular compartments of myelinating glia that are separated by layers of compact myelin. Gap junctions in myelinating glia regulate physiological processes such as cell growth, proliferation, calcium signaling, and participate in extracellular signaling via release of neurotransmitters from hemijunctions. In the CNS, gap junctions form a glial network between oligodendrocytes and astrocytes. This transcellular communication is hypothesized to maintain homeostasis by facilitating restoration of membrane potential after axonal activity via electrical coupling and the re-distribution of potassium ions released from axons. The generation of transgenic mice for different subsets of connexins has revealed the contribution of different connexins in gap junction formation and illuminated new subcellular mechanisms underlying demyelination and cognitive defects. Alterations in metabolic coupling have been reported in animal models of X-linked Charcot–Marie–Tooth disease (CMTX) and Pelizaeus–Merzbarcher-like disease (PMLD), which are caused by mutations in the genes encoding for connexin 32 and connexin 47 respectively. Future research identifying the expression and regulation of gap junctions in myelinating glia is likely to provide a better understanding of myelinating glia in nervous system function, plasticity, and disease. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Gap junction communication is crucial for myelination and axonal survival in the PNS and CNS. ► Gap junctions form a panglial syncytium between oligodendrocytes and astrocytes. ► They couple groups of cells together generating communication compartments. ► Connexons contribute to extracellular signaling via release of neurotransmitters. ► Mutations in connexin proteins change the properties and regulation of gap junctions.
Keywords: Abbreviations; A; astrocyte; O; oligodendrocyte; KO; knockout; dKO; double knockoutGap junction; Hemichannel; Myelinating glia; Intercellular communication; CMTX; PMLD
The participation of plasma membrane hemichannels to purinergic signaling by Alberto Baroja-Mazo; Barbera-Cremades Maria Barberà-Cremades; Pelegrin Pablo Pelegrín (pp. 79-93).
The field of hemichannels is closely related to the purinergic signaling and both areas have been growing in parallel. Hemichannels open in response to a wide range of stressful conditions, such as ischemia, pressure or swelling. Hemichannels represent an important mechanism for the cellular release of adenosine 5′-triphosphate (ATP), which is an agonist of the P2Y and P2X family of purinergic receptors. Therefore, hemichannels are key molecules in the regulation of purinergic receptor activation, during physiological and pathophysiological conditions. Furthermore, purinergic receptor activation can also lead to the opening of hemichannels and the subsequent amplification of purinergic signaling via a positive signaling feedback loop, giving rise to the concept of ATP-induced ATP release. Purinergic receptor signaling is involved in regulating many physiological and pathophysiological processes. P2Y receptors activate inositol trisphosphate and transiently increase intracellular calcium. This signaling opens both connexin and pannexin channels, therefore contributing to the expansion of calcium waves across astrocytes and epithelial cells. In addition, several of the P2X receptor subtypes, including the P2X2, P2X4 and P2X7 receptors, activate select cellular permeation pathways to large molecules, including the pannexin-1 channels, which are involved in the initiation of inflammatory responses and cell death. Consequently, the interplay between purinergic receptors and hemichannels could represent a novel target with substantial therapeutic implications in areas such as chronic pain, inflammation or atherosclerosis. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.► Pannexin and connexin hemichannels represent an important route for ATP release. ► Purinergic P2Y receptors activate hemichannels to propagate inter-cellular calcium waves. ► P2X7 receptors activate multiple cell permeabilization pathways, including pannexin-1 hemichannels. ► Purinergic activation of hemichannels could represent a novel permeation pathway for different signaling metabolites.
Keywords: Abbreviations; αβmeATP; α,β-methylene ATP; APC; Antigen presenting cell; ATP; Adenosine 5′-triphosphate; BCECs; Bovine corneal endothelial cells; BzATP; 2′,3′-; O; -(benzoyl-4-benzoyl)-ATP; cAMP; Cyclic adenosine 5′-monophasphate; CD39; ENTPD1; CD73; NT5E; CNS; Central nervous system; Cx; Connexin; DAMP; Danger associated molecular pattern; EC; Endothelia cell; EET; Epoxyeicosatrienoic acid; ENTPD1; Ecto-nucleoside triphosphate diphosphohydrolase 1; ERK; Extracellular signal-regulated protein kinases; IHC; Inner hair cells; IP3; Inositol trisphosphate; MAPK; Mitogen activated protein kinase; MHC; Major histocompatibility complex; NMDG; N; -methyl-; d; -glucamine; NO; Nitric oxide; NT5E; Ecto-5′-nucleotidase; OHC; Outer hair cells; OoC; Organ of Corti; PAMP; Pathogen associated molecular pattern; PLC; Phospholipase C; PPADS; pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid; RhoA; Ras homolog gene family member A; SMC; Smooth muscle cells; TCR; T-cell receptor; TM; Transmembrane; TNP-ATP; 2′,3′-; O; -(2,4,6-Trinitrophenyl)-ATP; VCAM-1; Vascular cell adhesion molecule 1Adenosine receptor; P2X receptor; P2Y receptor; Pannexin; Connexin; ATP release
Gap junction proteins on the move: Connexins, the cytoskeleton and migration by Linda Matsuuchi; Christian C. Naus (pp. 94-108).
Connexin43 (Cx43) has roles in cell–cell communication as well as channel independent roles in regulating motility and migration. Loss of function approaches to decrease Cx43 protein levels in neural cells result in reduced migration of neurons during cortical development in mice and impaired glioma tumor cell migration. In other cell types, correlations between Cx43 expression and cell morphology, adhesion, motility and migration have been noted. In this review we will discuss the common themes that have been revealed by a detailed comparison of the published results of neuronal cells with that of other cell types. In brief, these comparisons clearly show differences in the stability and directionality of protrusions, polarity of movement, and migration, depending on whether a) residual Cx43 levels remain after siRNA or shRNA knockdown, b) Cx43 protein levels are not detectable as in cells from Cx43−/− knockout mice or in cells that normally have no endogenous Cx43 expression, c) gain-of-function approaches are used to express Cx43 in cells that have no endogenous Cx43 and, d) Cx43 is over-expressed in cells that already have low endogenous Cx43 protein levels. What is clear from our comparisons is that Cx43 expression influences the adhesiveness of cells and the directionality of cellular processes. These observations are discussed in light of the ability of cells to rearrange their cytoskeleton and move in an organized manner. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Connexin43 regulates cell motility and migration. ► Gap junction proteins participate in channel and non-channel functions. ► Connexin43 expression influences process extension and cell polarity.
Keywords: Connexin43; Cytoskeleton; Polarity; Adhesion; Migration
Gap junction proteins: Master regulators of the planarian stem cell response to tissue maintenance and injury by T. Harshani Peiris; Néstor J. Oviedo (pp. 109-117).
Gap junction (GJ) proteins are crucial mediators of cell–cell communication during embryogenesis, tissue regeneration and disease. GJ proteins form plasma membrane channels that facilitate passage of small molecules across cells and modulate signaling pathways and cellular behavior in different tissues. These properties have been conserved throughout evolution, and in most invertebrates GJ proteins are known as innexins. Despite their critical relevance for physiology and disease, the mechanisms by which GJ proteins modulate cell behavior are poorly understood. This review summarizes findings from recent work that uses planarian flatworms as a paradigm to analyze GJ proteins in the complexity of the whole organism. The planarian model allows access to a large pool of adult somatic stem cells (known as neoblasts) that support physiological cell turnover and tissue regeneration. Innexin proteins are present in planarians and play a fundamental role in controlling neoblast behavior. We discuss the possibility that GJ proteins participate as cellular sensors that inform neoblasts about local and systemic physiological demands. We believe that functional analyses of GJ proteins will bring a complementary perspective to studies that focus on the temporal expression of genes. Finally, integrating functional studies along with molecular genetics and epigenetic approaches would expand our understanding of cellular regulation in vivo and greatly enhance the possibilities for rationally modulating stem cell behavior in their natural environment. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.► We use planarians to understand gap junction mediated stem cell regulation. ► A specific innexin protein regulates stem cell proliferation and response to injury. ► Gap junction and neural‐mediated signals control establishment of A/P axis. ► Gap junction proteins mediate short and long‐range signals that control SC behavior.
Keywords: Regeneration; Stem cell; Planarian; Innexin; Gap junction protein
Regulation of connexin expression by transcription factors and epigenetic mechanisms by Masahito Oyamada; Kumiko Takebe; Yumiko Oyamada (pp. 118-133).
Gap junctions are specialized cell–cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of metabolites and ions from one cell to another. Discoveries of human genetic disorders due to mutations in gap junction protein (connexin [Cx]) genes and experimental data on connexin knockout mice provide direct evidence that gap junctional intercellular communication is essential for tissue functions and organ development, and that its dysfunction causes diseases. Connexin-related signaling also involves extracellular signaling (hemichannels) and non-channel intracellular signaling. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including histone modifications, DNA methylation, and microRNA. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.►Gap junctions are specialized communicating cell–cell junctions made of connexins. ►Thus far, 21 human genes and 20 mouse genes for connexins have been identified. ►Connexin expression is regulated by transcription factors and epigenetic mechanisms.
Keywords: Connexin; Epigenetic regulation; Gap junction; Gene regulation; Transcription factor
Gap junction-mediated electrical transmission: Regulatory mechanisms and plasticity by Alberto E. Pereda; Sebastian Curti; Gregory Hoge; Roger Cachope; Carmen E. Flores; John E. Rash (pp. 134-146).
The term synapse applies to cellular specializations that articulate the processing of information within neural circuits by providing a mechanism for the transfer of information between two different neurons. There are two main modalities of synaptic transmission: chemical and electrical. While most efforts have been dedicated to the understanding of the properties and modifiability of chemical transmission, less is still known regarding the plastic properties of electrical synapses, whose structural correlate is the gap junction. A wealth of data indicates that, rather than passive intercellular channels, electrical synapses are more dynamic and modifiable than was generally perceived. This article will discuss the factors determining the strength of electrical transmission and review current evidence demonstrating its dynamic properties. Like their chemical counterparts, electrical synapses can also be plastic and modifiable. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Electrical synapses are dynamic and modifiable forms of interneuronal communication. ► The strength of electrical coupling is affected by gap junctional and non-junctional factors. ► Gap junctional conductance is dynamically regulated by nearby glutamatergic synapses. ► PKA and CaMKII, which regulate chemical synapses, also regulate electrical synapses. ► Gap junction regulation necessarily involves the interaction of gap junction channels with scaffold and regulatory proteins.
Keywords: Electrical synapse; Connexin 36; Synaptic plasticity; Electrical coupling; Auditory; Synchronization
Effects of mechanical forces and stretch on intercellular gap junction coupling by Aida Salameh; Stefan Dhein (pp. 147-156).
Mechanical forces provide fundamental physiological stimulus in living organisms. Recent investigations demonstrated how various types of mechanical load, like strain, pressure, shear stress, or cyclic stretch can affect cell biology and gap junction intercellular communication (GJIC). Depending on the cell type, the type of mechanical load and on strength and duration of application, these forces can induce hypertrophic processes and modulate the expression and function of certain connexins such as Cx43, while others such as Cx37 or Cx40 are reported to be less mechanosensitive. In particular, not only expression but also subcellular localization of Cx43 is altered in cardiomyocytes submitted to cyclic mechanical stretch resulting in the typical elongated cell shape with an accentuation of Cx43 at the cell poles. In the heart both cardiomyocytes and fibroblasts can alter their GJIC in response to mechanical load. In the vasculature both endothelial cells and smooth muscle cells are subject to strain and cyclic stretch resulting from the pulsatile flow. In addition, vascular endothelial cells are mainly affected by shear stress resulting from the blood flow parallel to their surface. These mechanical forces lead to a regulation of GJIC in vascular tissue. In bones, osteocytes and osteoblasts are coupled via gap junctions, which also react to mechanical forces. Since gap junctions are involved in regulation of cell growth and differentiation, the mechanosensitivity of the regulation of these channels might open new perspectives to explain how cells can respond to mechanical load, and how stretch induces self-organization of a cell layer which might have implications for embryology and the development of organs. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Cells can be affected by pressure, cyclic and static stretch, strain, shear stress. ► In this review, we describe how these various mechanical forces can be sensed by cells. ► We review how these mechanical forces lead to changes in the intercellular communication. ► This process leads to re-arrangement of cells and to changes in the cell's functional orientation. ► These processes are important for general understanding of cell biology and organ development.
Keywords: Stretch; Shear stress; Gap junction; Connexin; Heart; Vasculature
Connexins in atherosclerosis by Anna Pfenniger; Marc Chanson; Brenda R. Kwak (pp. 157-166).
Atherosclerosis, a chronic inflammatory disease of the vessel wall, involves multiple cell types of different origins, and complex interactions and signaling pathways between them. Autocrine and paracrine communication pathways provided by cytokines, chemokines, growth factors and lipid mediators are central to atherogenesis. However, it is becoming increasingly recognized that a more direct communication through both hemichannels and gap junction channels formed by connexins also plays an important role in atherosclerosis development. Three main connexins are expressed in cells involved in atherosclerosis: Cx37, Cx40 and Cx43. Cx37 is found in endothelial cells, monocytes/macrophages and platelets, Cx40 is predominantly an endothelial connexin, and Cx43 is found in a large variety of cells such as smooth muscle cells, resident and circulating leukocytes (neutrophils, dendritic cells, lymphocytes, activated macrophages, mast cells) and some endothelial cells. Here, we will systematically review the expression and function of connexins in cells and processes underlying atherosclerosis. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.► Connexins (Cxs) and gap junctions are involved in atherogenesis. ► Cx expression and function are regulated in all cell types involved in atherosclerosis. ► Cx37 and Cx40 are atheroprotective proteins; the role of Cx43 is less clear. ► A polymorphism in the human Cx37 gene is a prognostic marker for CAD.
Keywords: Gap junction; Connexin; Hemichannel; Atherosclerosis
The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations by Ji Xu; Bruce J. Nicholson (pp. 167-178).
Defects in several different connexins have been associated with several different diseases. The most common of these is deafness, where a few mutations in connexin (Cx) 26 have been found to contribute to over 50% of the incidence of non-syndromic deafness in different human populations. Other mutations in Cx26 or Cx30 have also been associated with various skin phenotypes linked to deafness (palmoplanta keratoderma, Bart–Pumphrey syndrome, Vohwinkel syndrome, keratitis–ichthyosis–deafness syndrome, etc.). The large array of disease mutants offers unique opportunities to gain insights into the underlying function of gap junction proteins and their channels in the normal and pathogenic physiologies of the cochlea and epidermis. This review focuses on those mutants where the impact on channel function has been assessed, and correlated with the disease phenotype, or organ function in knock-out mouse models. These approaches have provided evidence supporting a role of gap junctions and hemichannels in K+ removal and recycling in the ear, as well as possible roles for nutrient passage, in the cochlea. In contrast, increases in hemichannel opening leading to increased cell death, were associated with several keratitis–ichthyosis–deafness syndrome skin disease/hearing mutants. In addition to providing clues for therapeutic strategies, these findings allow us to better understand the specific functions of connexin channels that are important for normal tissue function. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.► Disease mutants provide insights into gap junction function in ear/skin function. ► Selective loss of IP3 permeability in NSHL, implicates Ca++ waves in normal hearing. ► Increased hemichannel activity causes cell death associated with dominant skin disease.
Keywords: Connexin 26; Connexin 30; Deafness; Skin disease; K; +; recycling; Hemichannel