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BBA - Biomembranes (v.1818, #8)

Editorial Board (pp. i).

The communicating junctions, composition, structure and characteristics by Herve Jean-Claude Hervé (pp. 1803-1806).

Voltage-dependent conformational changes in connexin channels by Thaddeus A. Bargiello; Qingxiu Tang; Seunghoon Oh; Taekyung Kwon (pp. 1807-1822).

Channels formed by connexins display two distinct types of voltage-dependent gating, termed V_j- or fast-gating and loop- or slow-gating. Recent studies, using metal bridge formation and chemical cross-linking have identified a region within the channel pore that contributes to the formation of the loop-gate permeability barrier. The conformational changes are remarkably large, reducing the channel pore diameter from 15 to 20Å to less than 4Å. Surprisingly, the largest conformational change occurs in the most stable region of the channel pore, the 3₁₀ or parahelix formed by amino acids in the 42–51 segment. The data provide a set of positional constraints that can be used to model the structure of the loop-gate closed state. Less is known about the conformation of the V_j-gate closed state. There appear to be two different mechanisms; one in which conformational changes in channel structure are linked to a voltage sensor contained in the N-terminus of Cx26 and Cx32 and a second in which the C-terminus of Cx43 and Cx40 may act either as a gating particle to block the channel pore or alternatively to stabilize the closed state. The later mechanism utilizes the same domains as implicated in effecting pH gating of Cx43 channels. It is unclear if the two V_j-gating mechanisms are related or if they represent different gating mechanisms that operate separately in different subsets of connexin channels. A model of the V_j-closed state of Cx26 hemichannel that is based on the X-ray structure of Cx26 and electron crystallographic structures of a Cx26 mutation suggests that the permeability barrier for V_j-gating is formed exclusively by the N-terminus, but recent information suggests that this conformation may not represent a voltage-closed state. Closed state models are considered from a thermodynamic perspective based on information from the 3.5Å Cx26 crystal structure and molecular dynamics (MD) simulations. The applications of computational and experimental methods to define the path of allosteric molecular transitions that link the open and closed states are discussed. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Voltage is an important regulator of connexin channel open probability. ► Conformational changes in two distinct voltage-gating mechanisms are reviewed. ► Computational methods to establish the path of molecular transitions are discussed.

Keywords: Ion channel; Gap junction; Voltage-dependent gating; Cadmium metal-bridge; Structure–function; Molecular dynamics

Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure by Eric C. Beyer; Gregory M. Lipkind; John W. Kyle; Viviana M. Berthoud (pp. 1823-1830).

The amino terminal domain (NT) of the connexins consists of their first 22–23 amino acids. Site-directed mutagenesis studies have demonstrated that NT amino acids are determinants of gap junction channel properties including unitary conductance, permeability/selectivity, and gating in response to transjunctional voltage. The importance of this region has also been emphasized by the identification of multiple disease-associated connexin mutants affecting amino acid residues in the NT region. The first part of the NT is α-helical. The structure of the Cx26 gap junction channel shows that the NT α-helix localizes within the channel, and lines the wall of the pore. Interactions of the amino acid residues in the NT with those in the transmembrane helices may be critical for holding the channel open. The predicted sites of these interactions and the applicability of the Cx26 structure to the NT of other connexins are considered. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► The amino terminal (NT) domain of the connexins consists of their first 22–23 amino acids. ► Many NT amino acids are conserved in different connexins. ► The first part of the NT is α-helical, and it lines the wall of the pore. ► NT amino acids are determinants of several channel properties. ► Disease-associated mutations have been identified throughout the connexin NT.

Keywords: Abbreviations; Amino terminal domain; NT; Connexin; Cx; Transmembrane domain; TM; Transjunctional voltage; V; _j; Nuclear magnetic resonance; NMRGap junction; Intercellular communication; Connexin

The connexin43 carboxyl terminus and cardiac gap junction organization by Joseph A. Palatinus; J. Matthew Rhett; Robert G. Gourdie (pp. 1831-1843).

The precise spatial order of gap junctions at intercalated disks in adult ventricular myocardium is thought vital for maintaining cardiac synchrony. Breakdown or remodeling of this order is a hallmark of arrhythmic disease of the heart. The principal component of gap junction channels between ventricular cardiomyocytes is connexin43 (Cx43). Protein–protein interactions and modifications of the carboxyl-terminus of Cx43 are key determinants of gap junction function, size, distribution and organization during normal development and in disease processes. Here, we review data on the role of proteins interacting with the Cx43 carboxyl-terminus in the regulation of cardiac gap junction organization, with particular emphasis on Zonula Occludens-1. The rapid progress in this area suggests that in coming years we are likely to develop a fuller understanding of the molecular mechanisms causing pathologic remodeling of gap junctions. With these advances come the promise of novel approach to the treatment of arrhythmia and the prevention of sudden cardiac death. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Keywords: Abbreviations; Aa; amino acid; CT; Carboxyl-Terminal; CL; Cytoplasmic loop; Cx43; Connexin 43; Dlg; Disks Large; GJ; Gap Junction; LSCM; Laser Scanning Confocal Microscope; NT; Amino Terminal; MAGUK; Membrane-Associated Guanylate Kinase; ODDD; oculodentodigital dysplasia; PDZ; Postsynaptic density/Disks large/ZO-1; UKS; Unknown Significance; ZO-1; Zonula-Occludens-1Connexin 43; Carboxyl terminus; Gap junction; ZO-1; Intercalated disk

Gap junctional channels are parts of multiprotein complexes by Herve Jean-Claude Hervé; Mickaël Derangeon; Denis Sarrouilhe; Ben N.G. Giepmans; Nicolas Bourmeyster (pp. 1844-1865).

Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton. Protein–protein interactions play essential roles in channel localization and activity and, besides their cell-to-cell channel-forming functions, gap junctional proteins now appear involved in different cellular functions ( e.g. transcriptional and cytoskeletal regulations). The present review summarizes the recent progress regarding the proteins capable of interacting with junctional proteins and highlights the function of these protein–protein interactions in cell physiology and aberrant function in diseases. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.► Gap junctional structures are transmembrane channels made by connexins, innexins or pannexins. ► They mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. ► We overviewed the proteins interacting with gap junctional proteins and examined the functional implications.

Keywords: Abbreviations of cell lines; 42GPA9; mouse Sertoli cell line; βTC-3; mouse pancreatic β cell line derived from insulinomas; A431; human squamous carcinoma cells; A7r5; rat aortic smooth muscle cell line; BICR/M1R; _k; a permanently growing cell line derived from a spontaneous rat mammary tumor; BWEM; rat cardiomyocyte-derived cells; C2C12; murine myoblasts; C6; rat glioma cell line; CHST8 cells; immortalized mouse hepatocytes; COS7; monkey African green kidney cells; E36; Chinese hamster ovary cells; FT210; a mutant cell line derived from FM3A a murine mammary carcinoma cell line; HEK 293; human embryonic kidney 293 cells; IAR20; rat epithelial cell line; J774; murine macrophage cell line; Jeg3; human choriocarcinoma cell line; LNCaP; human prostate cancer epithelial cells; MDCK; epithelial Madin–Darby Canine Kidney cells; Neuro2A; mouse neuroblastoma cells; N/N1003A; rabbit lens epithelial cells; NIH 3T3; mouse fibroblasts; NRK; rat kidney cells; N2a; murine neuroblastoma cells; P3/22; mouse skin papilloma cell line and its derivatives P3E1 (in which E-cadherin gene is transfected); PC-12 cell; a cell line substitute neuron originally cloned from rat pheochromocytoma cells; ROS 17/2.8; rat osteosarcoma cells; S180; mouse sarcoma cells; SW-13; human adrenal cortical tumor cells; T51B; rat liver epithelial cells; TtT/GF; murine pituitary folliculo-stellate-like cell line; U251; human glioblastoma cells; WB-F344; rat liver epithelial cellsConnexin; Pannexin; Innexin; Zonula Occludens; Protein–protein

The modulation of gap-junctional intercellular communication by lipid rafts by Norah Defamie; Marc Mesnil (pp. 1866-1869).

Lipid rafts are specific microdomains of plasma membrane which are enriched in cholesterol and sphingolipids. These domains seem to favour the interactions of particular proteins and the regulation of signalling pathways in the cells. Recent data have shown that among the proteins, which are preferentially localized in lipid rafts, are connexins that are the structural proteins of gap junctions. Since gap junctional intercellular communication is involved in various cellular processes and pathologies such as cancer, we were interested to review the various observations concerning this specific localization of connexins in lipid rafts and its consequences on gap junctional intercellular communication capacity. In particular, we will focus our discussion on the role of the lipid raft–connexin connection in cancer progression. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► The various observations concerning the localization of connexins in lipid rafts. ► Its consequences on GJIC regulation. ► The role of the lipid raft–connexin connection in cancer progression

Keywords: Cancer; Caveolae; Connexin; Gap junctional intercellular communication; Lipid raft

Endocytosis and post-endocytic sorting of connexins by Edward Leithe; Solveig Sirnes; Tone Fykerud; Ane Kjenseth; Edgar Rivedal (pp. 1870-1879).

The connexins constitute a family of integral membrane proteins that form intercellular channels, enabling adjacent cells in solid tissues to directly exchange ions and small molecules. These channels assemble into distinct plasma membrane domains known as gap junctions. Gap junction intercellular communication plays critical roles in numerous cellular processes, including control of cell growth and differentiation, maintenance of tissue homeostasis and embryonic development. Gap junctions are dynamic plasma membrane domains, and there is increasing evidence that modulation of endocytosis and post-endocytic trafficking of connexins are important mechanisms for regulating the level of functional gap junctions at the plasma membrane. The emerging picture is that multiple pathways exist for endocytosis and sorting of connexins to lysosomes, and that these pathways are differentially regulated in response to physiological and pathophysiological stimuli. Recent studies suggest that endocytosis and lysosomal degradation of connexins is controlled by a complex interplay between phosphorylation and ubiquitination. This review summarizes recent progress in understanding the molecular mechanisms involved in endocytosis and post-endocytic sorting of connexins, and the relevance of these processes to the regulation of gap junction intercellular communication under normal and pathophysiological conditions. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexins have high turnover rates in most tissue types. ► Multiple pathways exist for post-endocytic sorting of connexins to lysosomes. ► Degradation of connexins is regulated by phosphorylation and ubiquitination.

Keywords: Abbreviations; CHO; Chinese hamster ovary; CIP75; connexin43-interacting protein of 75-kDa; CIP85; connexin43-interacting protein of 85-kDa; Dab2; disabled-2; EEA1; early endosomal autoantigen 1; EGF; epidermal growth factor; ENaC; amiloride-sensitive epithelial sodium channel; ERAD; endoplasmic reticulum-associated degradation; ESCRT; endosomal sorting complex required for transport; HECT; homologous to E6-AP carboxy terminal; GPCR; G protein-coupled receptor; Hrs; hepatocyte growth factor-regulated tyrosine kinase substrate; MAPK; mitogen-activated protein kinase; Nedd4; neural precursor cell expressed, developmentally downregulated 4; NRK; normal rat kidney; OCP1; Organ of Corti protein 1; PLC β3; phospholipase Cβ3; PtdIns(4,5)P; ₂; phosphatidylinositol 4,5-bisphosphate; PKC; protein kinase C; RING; really interesting new gene; SCF; Skp1/Cul1/F-box complex; TPA; 12-; O; -tetradecanoylphorbol-13-acetate; Tsg101; tumor-susceptibility gene product 101; ZO-1; Zonula occludens 1Connexin; Gap junction; Endocytosis; Ubiquitin; Lysosome; Degradation

Nature of plasmalemmal functional “hemichannels” by Eliana Scemes (pp. 1880-1883).

The molecular identity of the protein forming “hemichannels” at non-junctional membranes is disputed. The family of gap junction proteins, innexins, connexins, and pannexins share several common features, including permeability characteristics and sensitivity to blocking agents. Such overlap in properties renders the identification of which of these protein species actually establishes the non-junctional membrane conductance and permeability quite complicated, especially because in vertebrates pannexins and connexins have largely overlapping distributions in tissues. Recently, attempts to establish criteria to identify events that are “hemichannel” mediated and those to allow the distinction between connexin- from pannexin-mediated events have been proposed.Here, I present an update on that topic and discuss the most recent findings related to the nature of functional “hemichannels” focusing on connexin43 and pannexin1. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Recent findings related to the nature of functional “hemichannels” are presented. ► Distinction between pannexons and connexons. ► “Hemichannels” assignment: evidences and controversies.

Keywords: Connexons; Pannexons; Panx1 channels; Cx43 hemichannel; Hemichannel assignment; Hemichannel properties

Modulation of metabolic communication through gap junction channels by transjunctional voltage; synergistic and antagonistic effects of gating and ionophoresis by Nicolás Palacios-Prado; Feliksas F. Bukauskas (pp. 1884-1894).

Gap junction (GJ) channels assembled from connexin (Cx) proteins provide a structural basis for direct electrical and metabolic cell–cell communication. Here, we focus on gating and permeability properties of Cx43/Cx45 heterotypic GJs exhibiting asymmetries of both voltage-gating and transjunctional flux ( J_j) of fluorescent dyes depending on transjunctional voltage ( V_j). Relatively small differences in the resting potential of communicating cells can substantially reduce or enhance this flux at relative negativity or positivity on Cx45 side, respectively. Similarly, series of V_j pulses resembling bursts of action potentials (APs) reduce J_j when APs initiate in the cell expressing Cx43 and increase J_j when APs initiate in the cell expressing Cx45. J_j of charged fluorescent dyes is affected by ionophoresis and V_j-gating and the asymmetry of J_j– V_j dependence in heterotypic GJs is enhanced or reduced when ionophoresis and V_j-gating work in a synergistic or antagonistic manner, respectively. Modulation of cell-to-cell transfer of metabolites and signaling molecules by V_j may occur in excitable as well as non-excitable tissues and may be more expressed in the border between normal and pathological regions where intercellular gradients of membrane potential and concentration of ions are substantially altered. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Heterotypic gap junction channels exhibit voltage gating and cell-to-cell signal transfer asymmetries. ► Transjunctional flux of fluorescent dyes was studied by combining dual whole-cell patch clamp and fluorescent imaging. ► Intercellular transfer of charged dyes is modulated by transjunctional voltage. ► Voltage-gating and ionophoresis can act on cell-cell metabolic communication in a synergistic or antagonistic manner.

Keywords: Connexin; Voltage gating; Dye transfer; Heterotypic channel; Signaling asymmetry; Transjunctional permeability and flux

Interaction between nitric oxide signaling and gap junctions: Effects on vascular function by R.C. Looft-Wilson; M. Billaud; S.R. Johnstone; A.C. Straub; B.E. Isakson (pp. 1895-1902).

Nitric oxide signaling, through eNOS (or possibly nNOS), and gap junction communication are essential for normal vascular function. While each component controls specific aspects of vascular function, there is substantial evidence for cross-talk between nitric oxide signaling and the gap junction proteins (connexins), and more recently, protein–protein association between eNOS and connexins. This review will examine the evidence for interaction between these pathways in normal and diseased arteries, highlight the questions that remain about the mechanisms of their interaction, and explore the possible interaction between nitric oxide signaling and the newly discovered pannexin channels. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► First review of eNOS and connexins. ► Schematic of the possible interplay between connexins/pannexins and NO in endothelium and smooth muscle. ► Pose questions for future research in vascular function and connexins.

Keywords: Endothelial nitric oxide synthase; Neuronal nitric oxide synthase; Connexin; Pannexin; Myoendothelial junction

Renal connexins and blood pressure by Armin Kurtz (pp. 1903-1908).

The kidneys are centrally involved in the regulation of blood pressure. Kidney function requires the coordinated actions of a number of different vascular and tubular cell types in the renal vasculature and in the renal tubular system. The intrarenal coordination of these actions is not well understood. Since gap junctions have been identified in the kidneys, possible pathways involved in this context could be direct intercellular communication via gap junctions or via connexin hemichannels. In this context nine different connexins have been found to be expressed in the kidney, either localized to the vasculature or to the tubular system. Evidence is arising that malfunctions of certain connexins have an impact on the capability of the kidney to maintain blood pressure homeostasis. Findings reported in this context will be outlined and discussed in this review. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Defective Cx40 function leads to hypertension. ► Cx40 is involved in the control of renin secretion. ► Cx30 is involved in renal salt handling.

Keywords: Sodium resorption; Cx30; Renin-angiotensin-system; Cx40; Hypertension; Cx40A96S mutation

Gap junctions and hemichannels in signal transmission, function and development of bone by Nidhi Batra; Rekha Kar; Jean X. Jiang (pp. 1909-1918).

Gap junctional intercellular communication (GJIC) mediated by connexins, in particular connexin 43 (Cx43), plays important roles in regulating signal transmission among different bone cells and thereby regulates development, differentiation, modeling and remodeling of the bone. GJIC regulates osteoblast formation, differentiation, survival and apoptosis. Osteoclast formation and resorptive ability are also reported to be modulated by GJIC. Furthermore, osteocytes utilize GJIC to coordinate bone remodeling in response to anabolic factors and mechanical loading. Apart from gap junctions, connexins also form hemichannels, which are localized on the cell surface and function independently of the gap junction channels. Both these channels mediate the transfer of molecules smaller than 1.2kDa including small ions, metabolites, ATP, prostaglandin and IP₃. The biological importance of the communication mediated by connexin-forming channels in bone development is revealed by the low bone mass and osteoblast dysfunction in the Cx43-null mice and the skeletal malformations observed in occulodentodigital dysplasia (ODDD) caused by mutations in the Cx43 gene. The current review summarizes the role of gap junctions and hemichannels in regulating signaling, function and development of bone cells. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Gap junctions and hemichannels in the bone cells ► Regulation of signaling by gap junctions and hemichannels in bone cells ► Gap junctions and hemichannels in mechanotransduction of the bone ► Connexins and bone development ► Connexins and stem cell differentiation

Keywords: Connexins; Gap junctions; Hemichannels; Mechanical stimulation; Osteoblast; Osteocyte

Connexin-dependent signaling in neuro-hormonal systems by Ilaria Potolicchio; Valentina Cigliola; Silvia Velazquez-Garcia; Philippe Klee; Amina Valjevac; Dina Kapic; Esad Cosovic; Orhan Lepara; Almira Hadzovic-Dzuvo; Zakira Mornjacovic; Paolo Meda (pp. 1919-1936).

The advent of multicellular organisms was accompanied by the development of short- and long-range chemical signalling systems, including those provided by the nervous and endocrine systems. In turn, the cells of these two systems have developed mechanisms for interacting with both adjacent and distant cells. With evolution, such mechanisms have diversified to become integrated in a complex regulatory network, whereby individual endocrine and neuro-endocrine cells sense the state of activity of their neighbors and, accordingly, regulate their own level of functioning. A consistent feature of this network is the expression of connexin-made channels between the (neuro)hormone-producing cells of all endocrine glands and secretory regions of the central nervous system so far investigated in vertebrates. This review summarizes the distribution of connexins in the mammalian (neuro)endocrine systems, and what we know about the participation of these proteins on hormone secretion, the life of the producing cells, and the action of (neuro)hormones on specific targets. The data gathered since the last reviews on the topic are summarized, with particular emphasis on the roles of Cx36 in the function of the insulin-producing beta cells of the endocrine pancreas, and of Cx40 in that of the renin-producing juxta-glomerular epithelioid cells of the kidney cortex. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexins and gap junctions are obligatory features of endocrine cells. ► Connexins contribute to control endocrine secretions. ► Connexins may also modulate the growth, differentiation and death of endocrine cells. ► The mechanisms involved are dependent on the cell-to-cell coupling. ► A pathophysiological role of connexins in endocrine diseases is suggested by correlative evidence.

Keywords: Endocrine gland; Hormone; Insulin; Renin; Cx36, Cx40, diabetes, hypertension

Gap junction-mediated intercellular communication in the adrenal medulla: An additional ingredient of stimulus–secretion coupling regulation by Claude Colomer; Agnès O. Martin; Desarmenien Michel G. Desarménien; Guerineau Nathalie C. Guérineau (pp. 1937-1951).

The traditional understanding of stimulus–secretion coupling in adrenal neuroendocrine chromaffin cells states that catecholamines are released upon trans-synaptic sympathetic stimulation mediated by acetylcholine released from the splanchnic nerve terminals. Although this statement remains largely true, it deserves to be tempered. In addition to its neurogenic control, catecholamine secretion also depends on a local gap junction-mediated communication between chromaffin cells. We review here the insights gained since the first description of gap junctions in the adrenal medullary tissue. Adrenal stimulus–secretion coupling now appears far more intricate than was previously envisioned and its deciphering represents a challenge for neurobiologists engaged in the study of the regulation of neuroendocrine secretion. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Several gap junctions are expressed in the adrenal medullary tissue. ► Adrenal gap junctional communication contributes to catecholamine release. ► Gap junctional coupling and synaptic transmission are functionally interconnected. ► Changes in stimulus–secretion coupling induce gap junctional coupling remodeling.

Keywords: Gap junctional remodeling; Adrenal medullary tissue; Stimulus–secretion coupling; Catecholamine release; Stress; Postnatal development

Connexins in epidermal homeostasis and skin disease by Claire A. Scott; Daniel Tattersall; Edel A. O'Toole; David P. Kelsell (pp. 1952-1961).

The expression of multiple connexin (Cx) types in the epidermis, their differential expression during wound closure and the association of skin pathology with specific Cx gene mutations, are indicative of important functions for Cxs in the skin. In this review, we focus on the role of Cx proteins in the epidermis and during wound healing and discuss mutations in Cx genes which cause skin disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Multiple connexins (Cx) are mutated in a spectrum of epidermal disorders. ► Cxs play a role in cutaneous wound healing. ► Endoplasmic reticulum stress is linked to erythrokeratoderma variabilis Cx31 mutants.

Keywords: Abbreviations; BL; basal layer; BPS; Bart–Pumphrey syndrome; CT; C-terminus; Cx; connexin; EKV; erythrokeratoderma variabilis; EL; extracellular loop; ER; endoplasmic reticulum; GJ; gap junction; GJIC; gap junction intercellular communication; GL; granular layer; HED; hidrotic ectodermal dysplasia; HID; hystrix-like ichthyosis–deafness; KID; keratitis–ichthyosis–deafness; NSHL; non-syndromic hearing loss; NT; N-terminus; ODDD; oculodentodigital dysplasia; PPK; palmoplantar keratoderma; SC; stratum corneum; SL; spinous layer; UPR; unfolded protein response; UTR; untranslated region; VS; Vohwinkel syndromeConnexin; Erythrokeratoderma variabilis; Gap junction; Keratinocyte; Skin

Connexin and pannexin as modulators of myocardial injury by Rodriguez-Sinovas Antonio Rodríguez-Sinovas; Sanchez Jose A. Sánchez; Celia Fernandez-Sanz; Marisol Ruiz-Meana; Garcia-Dorado David Garcia-Dorado (pp. 1962-1970).

Multicellular organisms have developed a variety of mechanisms that allow communication between their cells. Whereas some of these systems, as neurotransmission or hormones, make possible communication between remote areas, direct cell-to-cell communication through specific membrane channels keep in contact neighboring cells. Direct communication between the cytoplasm of adjacent cells is achieved in vertebrates by membrane channels formed by connexins. However, in addition to allowing exchange of ions and small metabolites between the cytoplasms of adjacent cells, connexin channels also communicate the cytosol with the extracellular space, thus enabling a completely different communication system, involving activation of extracellular receptors. Recently, the demonstration of connexin at the inner mitochondrial membrane of cardiomyocytes, probably forming hemichannels, has enlarged the list of actions of connexins. Some of these mechanisms are also shared by a different family of proteins, termed pannexins. Importantly, these systems allow not only communication between healthy cells, but also play an important role during different types of injury. The aim of this review is to discuss the role played by both connexin hemichannels and pannexin channels in cell communication and injury. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexins propagate death/survival between neighboring cells through gap junctions. ► Connexin and pannexin channels at the sarcolemma play a role in paracrine signaling. ► Connexin hemichannels participate in cell volume regulation and signaling cascades. ► Mitochondrial connexins have important consequences in cell physiology.

Keywords: Connexin; Hemichannel; Pannexin; Mitochondria; Gap junction; Edema

Functional redundancy and compensation among members of gap junction protein families? by Peter Bedner; Steinhauser Christian Steinhäuser; Martin Theis (pp. 1971-1984).

Gap junctions are intercellular conduits for small molecules made up by protein subunits called connexins. A large number of connexin genes were found in mouse and man, and most cell types express several connexins, lending support to the view that redundancy and compensation among family members exist. This review gives an overview of the current knowledge on redundancy and functional compensation — or lack thereof. It takes into account the different properties of connexin subunits which comprise gap junctional intercellular channels, but also the compatibility of connexins in gap junctions. Most insight has been gained by the investigation of mice deficient for one or more connexins and transgenic mice with functional replacement of one connexin gene by another. Most single deficient mice show phenotypical alterations limited to critical developmental time points or to specific organs and tissues, while mice doubly deficient for connexins expressed in the same cell type usually show more severe phenotypical alterations. Replacement of a connexin by another connexin in some cases gave rise to rescue of phenotypical alterations of connexin deficiencies, which were restricted to specific tissues. In many tissues, connexin substitution did not restore phenotypical alterations of connexin deficiencies, indicating that connexins are specialized in function. In some cases, fatal consequences arose from the replacement. The current consensus gained from such studies is that redundancy and compensation among connexins exists at least to a limited extent. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Gap junctions are made up by the large gene family of connexins. ► In most cell types, more than one connexin is expressed, supporting possible redundancy. ► By contrast, connexins may have unique and specialized functions. ► Here we critically examine redundancy and functional compensation among connexins in knockout and knock-in mice. ► We find redundant function and compensation is rare.

Keywords: Connexins; Pannexins; Intercellular communication; Transgenic mice

Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues by Marquez-Rosado Lucrecia Márquez-Rosado; Joell L. Solan; Clarence A. Dunn; Rachael P. Norris; Paul D. Lampe (pp. 1985-1992).

Gap junctions, composed of proteins from the connexin family, allow for intercellular communication between cells in essentially all tissues. There are 21 connexin genes in the human genome and different tissues express different connexin genes. Most connexins are known to be phosphoproteins. Phosphorylation can regulate connexin assembly into gap junctions, gap junction turnover and channel gating. Given the importance of gap junctions in development, proliferation and carcinogenesis, regulation of gap junction phosphorylation in response to wounding, hypoxia and other tissue insults is proving to be critical for cellular response and return to homeostasis. Connexin43 (Cx43) is the most widely and highly expressed gap junction protein, both in cell culture models and in humans, thus more research has been done on it and more reagents to it are available. In particular, antibodies that can report Cx43 phosphorylation status have been created allowing temporal examination of specific phosphorylation events in vivo. This review is focused on the use of these antibodies in tissue in situ, predominantly looking at Cx43 phosphorylation in brain, heart, endothelium and epithelium with reference to other connexins where data is available. These data allow us to begin to correlate specific phosphorylation events with changes in cell and tissue function. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexin phosphorylation regulates tissue function. ► Connexin phosphorylation is dynamic and changes during development. ► Connexin phosphorylation changes in tissue in response to wounding, ischemia and cellular transformation.

Keywords: Abbreviations; Cx; connexin; MAPK; mitogen-activated protein kinase; PKC; protein kinase C; PKA; protein kinase A; MEJ; myoendothelial junction; SDS-PAGE; sodium dodecylsulfate-polyacrylamide gel electrophoresis; VSMC; vascular smooth muscle cell; EC; endothelial cell; LH; luteinizing hormoneConnexin; Gap junction; Phosphorylation; Phosphospecific antibodies; Cell signalling

Channel-independent influence of connexin 43 on cell migration by Petra Kameritsch; Kristin Pogoda; Ulrich Pohl (pp. 1993-2001).

In this review we focus on the role of connexins, especially of Cx43, as modulators of migration — a fundamental process in embryogenesis and in physiologic functions of the adult organism. This impact of connexins is partly mediated by their function as intercellular channels but an increasing number of studies support the view that at least part of the effects are truly independent of the channel function. The channel-independent function comprises extrinsic guidance of migrating cells due to connexin mediated cell adhesion as well as intracellular processes. Cx43 has been shown to exert effects on migration by interfering with receptor signalling, cytoskeletal remodelling and tubulin dynamics. These effects are mainly dependent on the presence of the carboxyl tail of Cx43. The molecular basis of this channel-independent connexin function is still not yet fully understood but early results open an exciting view towards new functions of connexins in the cell. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.►We review the role of connexins in cell migration. ►We distinguish between channel-dependent and channel-independent effects of connexins on migration. ►We review molecular mechanism of intrinsic channel-independent connexin effects on migration.

Keywords: Connexin; Migration; Channel-dependent; Channel-independent

Non-channel functions of connexins in cell growth and cell death by Mathieu Vinken; Elke Decrock; Luc Leybaert; Geert Bultynck; Bernard Himpens; Tamara Vanhaecke; Vera Rogiers (pp. 2002-2008).

Cellular communication mediated by gap junction channels and hemichannels, both composed of connexin proteins, constitutes two acknowledged regulatory platforms in the accomplishment of tissue homeostasis. In recent years, an abundance of reports has been published indicating functions for connexin proteins in the control of the cellular life cycle that occur independently of their channel activities. This has yet been most exemplified in the context of cell growth and cell death, and is therefore as such addressed in the current paper. Specific attention is hereby paid to the molecular mechanisms that underpin the cellular non-channel roles of connexin proteins, namely the alteration of the expression of tissue homeostasis determinants and the physical interaction with cell growth and cell death regulators. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.►Connexins can control tissue homeostasis independently of their channel properties. ►Connexins can directly affect gene transcription. ►Connexins can physically interact with cell growth and cell death regulators.

Keywords: Abbreviations; ASK1; apoptosis signal-regulating kinase 1; CCN; cysteine rich 61, connective tissue growth factor and nephroblastoma overexpressed; Cx; connexin; Dlgh1; Discs-Large homolog 1; GJIC; gap junctional intercellular communication; NOV; nephroblastoma overexpressed; Wnt; Wingless-Int; ZO-1/2; zonula occludens 1/2; ZONAB; ZO-1-associated nucleic acid binding proteinConnexin; Cell growth; Cell death

Connexin43 phosphorylation and cytoprotection in the heart by Maya M. Jeyaraman; Wattamon Srisakuldee; Barbara E. Nickel; Elissavet Kardami (pp. 2009-2013).

The fundamental role played by connexins including connexin43 (Cx43) in forming intercellular communication channels (gap junctions), ensuring electrical and metabolic coupling between cells, has long been recognized and extensively investigated. There is also increasing recognition that Cx43, and other connexins, have additional roles, such as the ability to regulate cell proliferation, migration, and cytoprotection. Multiple phosphorylation sites, targets of different signaling pathways, are present at the regulatory, C-terminal domain of Cx43, and contribute to constitutive as well as transient phosphorylation Cx43 patterns, responding to ever-changing environmental stimuli and corresponding cellular needs. The present paper will focus on Cx43 in the heart, and provide an overview of the emerging recognition of a relationship between Cx43, its phosphorylation pattern, and development of resistance to injury. We will also review our recent work regarding the role of an enhanced phosphorylation state of Cx43 in cardioprotection. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexin43 is required to develop protein kinase C-mediated cytoprotection. ► Protective stimuli elicit Cx43 hyper-phosphorylation at specific sites. ► Cardioprotection-linked connexin43 phosphorylation is likely affecting several subcellular domains.

Keywords: Connexin43; PKC-mediated phosphorylation; Cytoprotection

Pathological hemichannels associated with human Cx26 mutations causing Keratitis–Ichthyosis–Deafness syndrome by Noah A. Levit; Gulistan Mese; Mena-George R. Basaly; Thomas W. White (pp. 2014-2019).

Connexin (Cx) proteins form intercellular gap junction channels by first assembling into single membrane hemichannels that then dock to connect the cytoplasm of two adjacent cells. Gap junctions are highly specialized structures that allow the direct passage of small molecules between cells to maintain tissue homeostasis. Functional activity of nonjunctional hemichannels has now been shown in several experimental systems. Hemichannels may constitute an important diffusional exchange pathway with the extracellular space, but the extent of their normal physiological role is currently unknown. Aberrant hemichannel activity has been linked to mutations of connexin proteins involved in genetic diseases. Here, we review a proposed role for hemichannels in the pathogenesis of Keratitis–Ichthyosis–Deafness (KID) syndrome associated with connexin26 (Cx26) mutations. Continued functional evaluation of mutated hemichannels linked to human hereditary disorders may provide additional insights into the mechanisms governing their regulation in normal physiology and dysregulation in disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Some skin disease-causing connexin mutations increase hemichannel activity. ► Hemichannels may play a role in pathophysiology of skin disease. ► Pharmacological blockade of hemichannels may provide novel therapeutic treatments.

Keywords: Connexin; Mutation; Genetic disease; Channel; Epidermis

Functional consequences of abnormal Cx43 expression in the heart by Magda S.C. Fontes; Toon A.B. van Veen; Jacques M.T. de Bakker; Harold V.M. van Rijen (pp. 2020-2029).

The major gap junction protein expressed in the heart, connexin43 (Cx43), is highly remodeled in the diseased heart. Usually, Cx43 is down-regulated and heterogeneously redistributed to the lateral sides of cardiomyocytes. Reverse remodeling of the impaired Cx43 expression could restore normal cardiac function and normalize electrical stability. In this review, the reduced and heterogeneous Cx43 expression in the heart will be addressed in hypertrophic, dilated and ischemic cardiomyopathy together with its functional consequences of conduction velocity slowing, dispersed impulse conduction, its interaction with fibrosis and propensity to generate arrhythmias. Finally, different therapies are discussed. Treatments aimed to improve the Cx43 expression levels show new potentially anti-arrhythmic therapies during heart failure, but those in the context of acute ischemia can be anti-arrhythmogenic at the cost of larger infarct sizes. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Review on the remodeling of cardiac ventricular gap junctions and its consequences. ► Heart remodeling results in heterogeneity and dephosphorylation of Cx43 expression. ► Consequences of abnormal Cx43 expression for the development of arrhythmias. ► Therapies aimed to improve the Cx43 expression levels, reduced arrhythmogenesis.

Keywords: Abbreviations; BZ; border zone; CV; conduction velocity; Cx43; connexin43; DCM; dilated cardiomyopathy; ERP; effective refractory period; HCM; hypertrophic cardiomyopathy; ICM; ischemic cardiomyopathy; IDs; intercalated disks; LV; left ventricleConnexin43; Heterogeneity; Arrhythmia; Conduction velocity; Fibrosis

Gap junctions in inherited human disorders of the central nervous system by Charles K. Abrams; Steven S. Scherer (pp. 2030-2047).

CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot–Marie–Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6months of life, cerebellar ataxia by 4years, and spasticity by 6years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann–Streiff syndrome, a disorder showing substantial overlap with ODDD. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.► Astrocytes express Cx30 and Cx43 and Oligodendrocytes express Cx29, Cx32, and Cx47. ► Mutations in GJB1, cause a form of Charcot–Marie–Tooth disease (CMT1X). Some patients have CNS signs and symptoms. ► Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease. ► A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis. ► Dominant mutations in GJA1, cause oculodentodigital dysplasia (ODDD). Spasticity and gait difficulties may be seen.

Keywords: Connexin; Gap junction; CMT1X; PMLD1; SPG44; ODDD

Glial connexin expression and function in the context of Alzheimer's disease by Annette Koulakoff; Xin Mei; Juan A. Orellana; Saez Juan C. Sáez; Christian Giaume (pp. 2048-2057).

A hallmark of neurodegenerative diseases is the reactive gliosis characterized by a phenotypic change in astrocytes and microglia. This glial response is associated with modifications in the expression and function of connexins (Cxs), the proteins forming gap junction channels and hemichannels. Increased Cx expression is detected in most reactive astrocytes located at amyloid plaques, the histopathological lesions typically present in the brain of Alzheimer's patients and animal models of the disease. The activity of Cx channels analyzed in vivo as well as in vitro after treatment with the amyloid β peptide is also modified and, in particular, hemichannel activation may contribute to neuronal damage. In this review, we summarize and discuss recent data that suggest glial Cx channels participate in the neurodegenerative process of Alzheimer's disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Reactive gliosis is a hallmark of Alzheimer's disease. ► Glial connexin expression is affected in this pathology. ► Connexins, but also pannexins hemichannels, are activated in glia. ► Astroglial connexins may contribute to neuronal damages in neurodegenerative diseases.

Keywords: Connexin; Astrocyte; Microglia; Hemichannel; Gap junction

Opposing roles of connexin43 in glioma progression by Wun-Chey Sin; Sophie Crespin; Marc Mesnil (pp. 2058-2067).

Despite the tremendous amount of data over the last 40years, lack of gap junctional intercellular communication (GJIC) or altered expression of gap junction proteins is still a lesser known ‘hallmark’ of cancer. Expression of astrocytic gap junction protein, connexin43 (Cx43), is often reduced in astrocytomas, the most common neoplasia of the central nervous system (CNS) in adults. Supported by a number of evidences, the global decrease of Cx43 expression appears to be advantageous for the growth of glioma cells. Although the mechanisms by which Cx43 regulates the expression levels of proteins involved in cell growth is unclear, there are evidences to suggest that it might be independent of their channel forming properties. In this regard, the carboxyl tail of Cx43 may have the ability to control the translocation of transcription factor regulators into the nucleus. However, this putative tumor suppressor effect of Cx43 is counterbalanced by its capacity to enhance the migration of glioma cells out of the tumor core through mechanisms that seems to implicate its carboxyl tail, possibly by interacting with the actin cytoskeleton. This ambivalence between the tumor suppressor effect and promotion of cell migration may partly be explained by the heterogeneous expression of Cx43 in the glioma core especially at the malignant glioblastoma stage; some tumor cells would be expected to migrate (Cx43 expressing cells) and others to proliferate (non-expressing Cx43 cells). Moreover, the involvement of Cx43 in glioma progression seems to be more complex since, in addition, GJIC may increase their resistance to apoptosis and Cx43 may also affect cell homeostasis in a paracrine fashion via hemichannel action. In conclusion, Cx43 appears to be involved at different levels of the glioma progression by acting on cell growth regulation, promotion of cell migration and resistance to apoptosis. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Connexin43 is aberrantly expressed in glioma. ► Molecular mechanisms involving connexin43 in glioma cell growth are described. ► Molecular mechanisms involving connexin43 in glioma migration are described. ► The regulation of apoptosis by connexin43 is described in glioma cells. ► Connexin43 is a pivotal protein involved in different phases of glioma progression.

Keywords: Abbreviations; CNS; Central nervous system; CSCs; Cancer stem cells; Cx43; Connexin43; EMT; Epithelial–mesenchymal transition; GBM; Glioblastoma multiform; GJIC; Gap junctional intercellular communication; GSH; Glutathione; NSCs; Neural stem cellsGlioma; Gap junctional intercellular communication; Connexin43; Cell growth; Migration; Apoptosis

Connexins in wound healing; perspectives in diabetic patients by David L. Becker; Christopher Thrasivoulou; Anthony R.J. Phillips (pp. 2068-2075).

Skin lesions are common events and we have evolved to rapidly heal them in order to maintain homeostasis and prevent infection and sepsis. Most acute wounds heal without issue, but as we get older our bodies become compromised by poor blood circulation and conditions such as diabetes, leading to slower healing. This can result in stalled or hard-to-heal chronic wounds. Currently about 2% of the Western population develop a chronic wound and this figure will rise as the population ages and diabetes becomes more prevalent . Patient morbidity and quality of life are profoundly altered by chronic wounds . Unfortunately a significant proportion of these chronic wounds fail to respond to conventional treatment and can result in amputation of the lower limb. Life quality and expectancy following amputation is severely reduced. These hard to heal wounds also represent a growing economic burden on Western society with published estimates of costs to healthcare services in the region of $25B annually . There exists a growing need for specific and effective therapeutic agents to improve healing in these wounds. In recent years the gap junction protein Cx43 has been shown to play a pivotal role early on in the acute wound healing process at a number of different levels []. Conversely, abnormal expression of Cx43 in wound edge keratinocytes was shown to underlie the poor rate of healing in diabetic rats, and targeting its expression with an antisense gel restored normal healing rates . The presence of Cx43 in the wound edge keratinocytes of human chronic wounds has also been reported . Abnormal Cx43 biology may underlie the poor healing of human chronic wounds and be amenable therapeutic intervention . This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Cx43 downregulates in wound edge keratinocytes and fibroblasts as they become migratory. ► Cx43 upregulates in blood vessels around a site of injury as they become inflamed and leaky. ► Actively reducing Cx43 in a wound speeds keratinocyte and fibroblast migration and healing whilst reducing inflammation. ► Preventing abnormal expression of Cx43 in the STZ diabetic rat wound edge keratinocytes rescues wound healing rates. ► Application of Cx43 antisense to venous leg ulcers significantly promotes their healing.

Keywords: Wound healing; Venous leg ulcer; Diabetic foot ulcer; Gap junction; Connexin 43; Nexagon

Can gap junctions deliver? by Peter R. Brink; Virginijus Valiunas; Chris Gordon; Michael R. Rosen; Ira S. Cohen (pp. 2076-2081).

In vivo delivery of small interfering RNAs (siRNAs) to target cells via the extracellular space has been hampered by dilution effects and immune responses. Gap junction-mediated transfer between cells avoids the extracellular space and its associated limitations. Because of these advantages cell based delivery via gap junctions has emerged as a viable alternative for siRNA or miRNA delivery. Here we discuss the advantages and disadvantages of extracellular delivery and cell to cell delivery via gap junction channels composed of connexins. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► Cellular delivery of siRNA in vivo ► Connexin mediated coupling a unique pathway for in vivo delivery ► Alternate delivery pathways: pinocytosis/endosomes/exosomes

Keywords: Cell based delivery; siRNA, miRNA; Gap junction; Exosomes; Endosomes

Long-distance electrical coupling via tunneling nanotubes by Xiang Wang; Hans-Hermann Gerdes (pp. 2082-2086).

Tunneling nanotubes (TNTs) are nanoscaled, F-actin containing membrane tubes that connect cells over several cell diameters. They facilitate the intercellular exchange of diverse components ranging from small molecules to organelles and pathogens. In conjunction with recent findings that TNT-like structures exist in tissue, they are expected to have important implications in cell-to-cell communication. In this review we will focus on a new function of TNTs, namely the transfer of electrical signals between remote cells. This electrical coupling is not only determined by the biophysical properties of the TNT, but depends on the presence of connexons interposed at the membrane interface between TNT and the connected cell. Specific features of this coupling are compared to conventional gap junction communication. Finally, we will discuss possible down-stream signaling pathways of this electrical coupling in the recipient cells and their putative effects on different physiological activities. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.► A novel function attributed to TNTs is the long-range spread of electrical signals. ► This function depends on the presence of connexons interposed into the TNT connection. ► The transmitted signals activate low voltage calcium channels in recipient cells. ► This results in transient calcium signals by local influx of calcium.

Keywords: Tunneling nanotube; TNT; Gap junction; Connexon; Long-distance electrical coupling; Intercellular communication

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