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PubMed2001

A neuroprotective role for gap junctions.

Glial-neuronal interactions have been implicated in both normal information processing and neuroprotection. One pathway of cellular interactions involves gap junctional intercellular communication (GJIC). In astrocytes, gap junctions are composed primarily of the channel protein, connexin43 (Cx43), and provide a substrate for formation of a functional syncytium implicated in the process of spatial buffering in the CNS. Thus gap junctional communication may be neuroprotective following a CNS insult that entails glutamate cytotoxicity (i.e. ischemia). We have shown that blocking gap junctions during a glutamate insult to co-cultures of astrocytes and neurons results in increased neuronal injury. To assess the effect of reduced Cx43 and GJIC on neuroprotection, we examined brain infarct volume in wild type and Cx43 heterozygote null mice following focal ischemia. Cx43 heterozygous null mice exhibited a significantly larger infarct volume compared to wild type. At the cellular level, a significant increase in TUNEL positive cells was observed in the penumbral region of the Cx43 heterozygote mice. These results suggest that augmentation of GJIC in astrocytes may contribute to neuroprotection following ischemic injury. These findings support the hypothesis that gap junctions play a neuroprotective role against glutamate cytotoxicity.

Animals↗
PubMed1995

Cardiac muscle cell interaction: from microanatomy to the molecular make-up of the gap junction.

Electrical coupling between cardiac muscle cells is mediated by specialised sites of plasma membrane interaction termed gap junctions, one of three types of intercellular junction of the cardiac intercalated disk. Gap junctions consist of clusters of plasma membrane channels directly linking the cytoplasmic compartments of neighbouring cells. Gap-junctional channels are constructed from connexins, a multigene family of conserved proteins. The principal connexin isoform of the mammalian heart is connexin43; other connexins, notably connexin40, connexin45 and connexin37, are also expressed but in smaller quantities. Antibodies directed against unique sequences of these molecules allow investigation of the role of gap junctions and their component connexins in relation to the electrophysiological properties of the healthy and diseased heart. Confocal laser scanning microscopy of working ventricular myocytes immunolabelled with anticonnexin43 antibodies permits highly sensitive detection of gap junctions, allowing detailed analysis of the spatial distribution of the conduction pathways from the level of the cell to that of the tissue as a whole. Gap junction distribution, number and regional variations in the type of connexin expressed all contribute to the uniform anisotropic pattern of impulse spread characteristic of normal myocardium and the orderly, sequential contraction of the cardiac chambers. Connexin40 is preferentially expressed by myocytes of the atrioventricular conduction system and represents a specialisation facilitating fast conduction, allowing rapid distribution of the impulse throughout the working ventricle. Two major abnormalities in connexin43 gap junctions are detected in human ischaemic heart disease. First, at border zones adjacent to infarct scars, zones which are particularly prone to re-entry arrhythmia, there is marked disruption of the usual ordered distribution pattern of gap junctions. Second, a widespread downregulation of connexin43 gap junctions occurs in myocardium distant from the infarct, a change that is also found in the hypertrophic (non-ischaemic) heart. Consequent localised heterogeneous conduction and reduced conduction velocity provide an explanation for the genesis of re-entry arrhythmias. A current working hypothesis is that reduction in connexin43 gap junctions is a general pathogenetic feature of cardiac disease which predisposes the heart to arrhythmia, and that this reduction may form part of a wider pattern of alteration in the levels of other connexin isoforms.

Animals↗
PubMed2006

Identification of the junctional plaque protein plakophilin 3 in cytoplasmic particles containing RNA-binding proteins and the recruitment of plakophilins 1 and 3 to stress granules.

Recent studies on the subcellular distribution of cytoplasmic plaque proteins of intercellular junctions have revealed that a number of such proteins can also occur in the cyto- and the nucleoplasm. This occurrence in different, and distant locations suggest that some plaque proteins play roles in cytoplasmic and nuclear processes in addition to their involvement in cell-cell adhesive interactions. Plakophilin (PKP) 3, a member of the arm-repeat family of proteins, occurs, in a diversity of cell types, both as an architectural component in plaques of desmosomes and dispersed in cytoplasmic particles. In immuno-selection experiments using PKP3-specific antibodies, we have identified by mass spectrometric analysis the following RNA-binding proteins: Poly (A) binding protein (PABPC1), fragile-X-related protein (FXR1), and ras-GAP-SH3-binding protein (G3BP). Moreover, the RNA-binding proteins codistributed after sucrose gradient centrifugation in PKP3-containing fractions corresponding to 25-35 S and 45-55 S. When cells are exposed to environmental stress (e.g., heat shock or oxidative stress) proteins FXR1, G3BP, and PABPC1 are found, together with PKP3 or PKP1, in "stress granules" known to accumulate stalled translation initiation complexes. Moreover, the protein eIF-4E and the ribosomal protein S6 are also detected in PKP3 particles. Our results show that cytoplasmic PKP3 is constitutively associated with RNA-binding proteins and indicate an involvement in processes of translation and RNA metabolism.

Caco-2 Cells↗
PubMed1989

The actions of retinoids on cellular growth correlate with their actions on gap junctional communication.

Retinoic acid (a possible morphogen), its biological precursor retinol, and certain synthetic derivatives of retinol profoundly change junctional intercellular communication and growth (saturation density) in 10T 1/2 and 3T3 cells and in their transformed counterparts. The changes correlate: growth decreases as the steady-state junctional permeability rises, and growth increases as that permeability falls. Retinoic acid and retinol exert quite different steady-state actions on communication at noncytotoxic concentrations in the normal cells: retinoic acid inhibits communication at 10(-10)-10(-9) M and enhances at 10(-9)-10(-7) M, whereas retinol only enhances (10(-8)-10(-6) M). In v-mos-transformed cells the enhancement is altogether lacking. But regardless of the retinoid or cell type, all growth responses show essentially the same dependence on junctional permeability. This is the expected behavior if the cell-to-cell channels of gap junctions disseminate growth-regulating signals through cell populations.

Animals↗
PubMed1980

Cell membrane features of rabbit arterial smooth muscle. A freeze-fracture study.

The cell membrane of smooth muscle cells from four large arteries of rabbits was investigated by freeze-fracture. On the surface of the smooth muscle smooth zones could be distinguished arranged in an alternate manner with zones characterised by numerous openings of surface vesicles. Vesiculate zones formed bands of variable width, generally parallel to the long axis of the cell, or irregular patches of different size. The density of vesicles within bands and patches varied from a very loose packing to a dense, quasi-hexagonal array. Comparative morphometric studies of the cell membrane replicas showed differences in the ratio vesiculate area: smooth area and also different surface vesicle frequencies expressed either as mean values or as values for vesiculate zones, in the arteries investigated. Communicating junctions (nexuses, gap junctions) characterized by a random arrangement of particles on the P-face and a more ordered, rhomboidal array of pits on the E-face were the only type of intercellular junctions found between arterial smooth muscle cells.

Animals↗
PubMed1993

Endothelial cell-to-cell junctions. Structural characteristics and functional role in the regulation of vascular permeability and leukocyte extravasation.

Endothelial monolayer forms the main barrier to the passage of macromolecules and circulating cells from blood to tissues. This property is regulated by intercellular junctions. These are complex structures formed by transmembrane adhesive molecules linked to a network of cytoplasmic cytoskeletal proteins. Endothelial junctions vary in number and organization along the vascular tree. Some transmembrane components of endothelial junctions have recently been identified. One is specifically expressed by endothelial cells (cadherin-5) while others (such as PECAM-1 and integrins) are also present in other cell types. The mechanisms that regulate the opening and the closure of endothelial junctions are still obscure. It is possible that inflammatory agents increase permeability by binding to specific receptors on the endothelial membrane. This would lead to the generation of intracellular signals causing cytoskeletal reorganization and opening of interendothelial gaps. This general sequence of events, however, seems to follow specific routes for different stimuli. In fact, permeability-increasing agents differ in the type of intracellular second messenger they trigger, for the time course of their effect, and for their specificity for the endothelium of different vascular districts. Endothelial junctions also regulate leukocyte extravasation. Endothelial cells actively contribute to this process by expressing adhesive molecules on their surface and by releasing chemotactic cytokines. Once leukocytes have adhered to the endothelium, a coordinated opening of interendothelial junctions occurs. The mechanism by which this takes place is unknown but it might resemble that triggered by soluble inflammatory mediators.

Amino Acid Sequence↗
PubMed1997

Testin is tightly associated with testicular cell membrane upon its secretion by sertoli cells whose steady-state mRNA level in the testis correlates with the turnover and integrity of inter-testicular cell junctions.

Testin, a Sertoli cell secretory protein whose mRNA is predominantly expressed in the testis, was shown to become tightly associated with Sertoli cell membrane upon its secretion whose solubilization requires the use of a detergent such as SDS. In the in vitro studies using Sertoli cells cultured at high cell density, where specialized junctions were being formed, the concentration of "soluble" testin in the spent media was greatly reduced versus monolayer cultures at low cell density, where specialized junctions were absent. Conversely, the concentration of "membrane-bound" testin from detergent-solubilized Sertoli cell membrane extract was positively correlated to the existence of specialized junctions in these cultures. In normal rat testes, the level of radioimmunoassayable soluble testin in the cytosol was low. However, when the inter-testicular cell junctions were disrupted either by a drug treatment such as lonidamine in vivo or by a physical treatment in vitro such as exposing Sertoli-germ cell co-cultures where specialized junctions were formed to a hypotonic treatment, a drastic surge in the testin gene expression was noted. Thus, testin can become tightly associated with Sertoli cell membrane upon its secretion when intercellular junctions are formed. It is also a marker to monitor the integrity of inter-testicular cell junctions.

Animals↗
PubMed1992

A chimeric N-cadherin/beta 1-integrin receptor which localizes to both cell-cell and cell-matrix adhesions.

To study the molecular mechanisms involved in formation of cell contacts, we have transfected cultured cells with a chimeric cDNA encoding the cytoplasmic and transmembrane domains of beta 1 integrin and the extracellular region of N-cadherin and determined the subcellular distribution of the chimeric molecule. We show that the chimeric receptor associates preferentially with cell-matrix focal contacts, suggesting that its distribution is directed by its beta 1 integrin segment, presumably via interactions of the cytoplasmic domain with cytoskeletal elements characteristic of focal contacts. Transfected cells which expressed relatively high levels of the cadherin/integrin chimera underwent an apparent epithelialization and contained the molecule both in cell-matrix and cell-cell contacts. Location in cell-cell contacts indicates competence of the cadherin extracellular domain to participate in formation of cell-cell junctions using a foreign cytoplasmic domain. Labeling of these cultures for talin, which is normally associated only with matrix adhesions, revealed specific labeling along the newly formed intercellular junctions. This suggests that the local association of talin with these sites is induced by the cytoplasmic tail of beta 1 integrin receptor presented by the chimeric protein. These results suggest that the formation of adherens-type junctions is driven by the cooperative interactions of the relevant adhesion molecules (cadherins and integrins) both with the respective extracellular ligands and with the cytoskeleton.

3T3 Cells↗
PubMed2000

The disruption of adherens junctions is associated with a decrease of E-cadherin phosphorylation by protein kinase CK2.

The down-regulation of E-cadherin is a common event in carcinogenesis. Phosphorylation/dephosphorylation is one posttranscriptional process which may regulate intercellular junctions. Here we show that in okadaic acid-treated keratinocytes, E-cadherin expression is shifted from the membrane to the cytoplasm, preventing cells from forming aggregates. These changes of E-cadherin localization and function are associated with a decrease in its phosphorylation state. The decrease in E-cadherin phosphorylation was essentially detected in okadaic acid-treated cell lysates isolated from 0.5% Triton-soluble fraction and not in the Triton-insoluble fraction linked to the cytoskeleton, suggesting a role of E-cadherin phosphorylation in cell-cell interactions. E-cadherin was markedly phosphorylated by CK2, either the purified recombinant enzyme or the endogenous enzyme. Using specific CK2 inhibitors such as heparin and 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole, endogenous CK2 was confirmed as the main enzyme phosphorylating E-cadherin. The decrease in E-cadherin phosphorylation by endogenous CK2 was not restored by the addition of purified CK2, confirming that it is not due to a defect in CK2 expression or to its reduced activity, but rather to the incapacity of CK2 to phosphorylate E-cadherin. The co-immunoprecipitation and colocalization of E-cadherin and CK2 suggests that CK2 may play a critical role in the maintenance of epidermis cohesion.

Cadherins↗
PubMed2000

Rab3B regulates ZO-1 targeting and actin organization in PC12 neuroendocrine cells.

Rab3B is a monomeric GTPase that modulates norepinephrine secretion when expressed in PC12 neuroendocrine cells. In the present study we determined whether rab3B also regulates the organization of intercellular junctions, since this GTPase localizes to regions of cell contact in multiple cell types. The stable expression of rab3B, but not the closely related rab3A, led to two morphological phenotypes in PC12 cells: (i) reorganization of F-actin into long filopodia and (ii) redistribution of the junction-associated protein ZO-1. ZO-1 localization was not appreciably affected by the expression of a GTP binding mutant of rab3B (N135I) that stimulates norepinephrine secretion by PC12 cells. The apparent diversity of these rab3B phenotypes implies that this GTPase is capable of influencing cell signaling pathways that in turn modulate the cytoskeleton and junction organization. In support of this hypothesis we observed that rab3B expression also altered the profile of proteins that interact with the signaling molecule, phosphatidylinositol 3-kinase (PI3-kinase). The effect of rab3B on protein interactions with PI3-kinase was reversed by inhibitors of this kinase. Furthermore, PI3-kinase inhibitors virtually abolished ZO-1 localization at the surfaces of cells that express rab3B, but not rab3A, whereas these inhibitors had no effect on rab3B-dependent norepinephrine secretion. Our results indicate that rab3B can influence junctional protein targeting and secretion by distinct mechanisms.

Actins↗
PubMed1979

In vivo negative staining of the midgut continuous junction in the mosquito, Culex tarsalis (Diptera: Culicidae).

The midguts of female mosquitoes, Culex tarsalis, were examined electron microscopically during the digestion of a meal from either artificial sources (i.e., 100% serum or defibrinated rabbit blood) or vertebrate hosts. Intense intercellular staining was apparent when the meal was derived from the vertebrate host or defibrinated rabbit blood; less intense staining with 100% serum. The staining was attributed to the "leakage" of a component of whole blood, presumably hemoglobin, into the intercellular junctional spaces. The staining component demonstrated an affinity for the outer membrane leaflet of the plasma membrane. This study provides evidence in support of "leaky guts" as a means of infecting an arthropod host without a midgut amplification cycle. The ramifications of this concept are pointed out with reference to vector competence and midgut barriers to infection by arboviruses.

Animal Feed↗
PubMed1999

Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells.

Proinflammatory cytokines such as TNF-alpha and IFN-gamma induce cell adhesion molecules in endothelial cells and promote transmigration of leukocytes across endothelial cells. However, when those two were administered together, leukocyte transmigration paradoxically decreased. We cloned a human and bovine homologue of the junctional adhesion molecule (JAM), a novel molecule at the tight junction, and examined the effects of proinflammatory cytokines on JAM in HUVECs. The combined treatment of TNF-alpha plus IFN-gamma caused a disappearance of JAM from intercellular junctions. However, flow cytometry, cell ELISA, and subcellular fractionation analysis demonstrated that the amount of JAM was not reduced. This suggested that JAM changed its distribution in response to proinflammatory cytokines. This redistribution of JAM might be involved in a decrease in transendothelial migration of leukocytes at inflammatory sites.

Amino Acid Sequence↗
PubMed1992

Gap junctions in myometrial cell cultures: evidence for modulation by cyclic adenosine 3':5'-monophosphate.

Primary cultures of myometrial cells from juvenile rats, continuous cultures maintained by serial passage, and a pSV3neotransfected myometrial cell line were established and utilized for the study of development and modulation of gap junctional intercellular communication (GJIC) in vitro. The smooth muscle origin and homogeneity of the cultures were verified by immunofluorescence staining of alpha-smooth muscle actin and cellular desmin. Although gap junctions were not detected in thin sections of juvenile and adult myometrial tissues by transmission electron microscopy, they were detected in cultured myometrial cells derived from juvenile and adult animals. The presence of GJIC in cultured cells was confirmed using a fluorescence recovery after photo-bleaching assay. Administration of exogenous estradiol-17 beta (10(-7) M) resulted in an increase in GJIC in primary and passage 9 myometrial cultures, whereas pSV3neo-transfected myometrial cells were not significantly different from untreated controls. The lack of estrogen responsiveness in pSV3neo-transfected cultures correlated with lower levels of estrogen receptors than in primary cultures. Addition of 1 mM 8-bromo-cAMP resulted in rapid (within 2 min) increases in dye transfer in both control and estradiol-17 beta-primed primary cultures. Uncoupling of cells by treatment with 1 mM 1-octanol, followed by addition of 1 mM 8-bromo-cAMP, resulted in increased GJIC in control and estradiol-17 beta-primed cultures, although up-regulation of GJIC in estradiol-17 beta-primed cultures was much greater than in control cultures. Comparative experiments carried out on a spontaneously immortalized rat granulosa cell line (SIGC), which expresses the same connexin43 species as myometrial cells, exhibited similar responses to exogenous 8-bromo-cAMP following uncoupling of gap junctions with octanol. While the results of these investigations may not be extrapolated to myometrium in vivo, they suggest that myometrial cell culture may offer additional opportunities to explore the temporal expression and modulation of GJIC in myometrium.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1980

Anatomic pathway of fluid leakage in fluid-overload pulmonary edema in mice.

Mice were given an intravenous injection of isotonic saline containing horseradish peroxidase (HRP) as an ultrastructural marker in an attempt to determine the site of fluid leakage from the vascular space to the air space in the lung. The localization of HRP was studied by ultrastructural histochemistry. When injected in a small volume of saline (0.1 ml), HRP was confined in the vascular space. When the volume of saline was increased to 1.0 ml, the reaction product of HRP was found first in the intercellular junctions of the arterial endothelium and then through the arterial wall. The reaction product was traced from the arterial wall to the peribronchiolar tissue, bronchiolar wall, and the intercellular space of the bronchiolar epithelium. HRP was seen in direct contact with the air space in the bronchiole. It is suggested that in fluid-overload pulmonary edema, fluid leaks through the arterial wall to the peribronchiolar tissue and then into the intercellular space of the bronchiolar epithelium. Alveolar is probably a result of the backflow of fluid from the bronchiole.

Animals↗
PubMed1985

Molecular heterogeneity of adherens junctions.

We describe here the subcellular distributions of three junctional proteins in different adherens-type contacts. The proteins examined include vinculin, talin, and a recently described 135-kD protein (Volk, T., and B. Geiger, 1984, EMBO (Eur. Mol. Biol. Organ.) J., 10:2249-2260). Immunofluorescent localization of the three proteins indicated that while vinculin was ubiquitously present in all adherens junctions, the other two showed selective and mutually exclusive association with either cell-substrate or cell-cell adhesions. Talin was abundant in focal contacts and in dense plaques of smooth muscle, but was essentially absent from intercellular junctions such as intercalated disks or adherens junctions of lens fibers. The 135-kD protein, on the other hand, was present in the latter two loci and was apparently absent from membrane-bound plaques of gizzard or from focal contacts. Radioimmunoassay of tissue extracts and immunolabeling of cultured chick lens cells indicated that the selective presence of talin and of the 135-kD protein in different cell contacts is spatially regulated within individual cells. On the basis of these findings it was concluded that adherens junctions are molecularly heterogeneous and consist of at least two major subgroups. Contacts with noncellular substrates contain talin and vinculin but not the 135-kD protein, whereas their intercellular counterparts contain the latter two proteins and are devoid of talin. The significance of these results and their possible relationships to contact-induced regulation of cell behavior are discussed.

Animals↗
PubMed1988

[Ultrastructural organization of the surface of the cingulate cortex of the cerebrum in rats].

In the cingulate cortex of rats the marginal glia is predominantly presented as fibrillar astrocytes, their bodies are situated immediately at the surface. Numerous axons, dendrites, synapses and myelinated fibers are often arranged near the very surface and are separated from it with only 1-2 thin processes of glial cells. Along the whole cortical surface one can see a limiting membrane--a layer of non-cellular substance, situating at the distance of 60-100 mcm from plasmalemmas of the marginal astrocytes. Using ruthenium red, it is possible to reveal the glycocalix layer on the surface of the limiting membrane, as well as cords of the electron opaque substance, that connect it with plasmolemma of the superficial astrocytes. Three types of the cingulate cortex surface are described in rats: superficial areas to which cells of the pia mater membrane adjoin; areas where cells of the pia mater membrane are situated at various distance from the cortical surface and areas of close adjoining of the right and left hemispheres of the cerebrum. Sometimes the cleft between the hemispheres is completely reduced, and narrow lamellar-like cells of the pia mater membrane are tightly inserted between the limiting membranes of both hemispheres or adjoin the blood vessel, situating between the hemispheres. At the surface numerous gap and desmosome-like junctions are observed. This is especially important at the border where the media are separated. At injection of neurotoxin 6-hydroxydopamine certain ultrastructural rearrangements are noted in cytoplasm of the marginal astrocytes, changes in the number and extension of intercellular junctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effect of perchloroethylene and its metabolites on intercellular communication in clone 9 rat liver cells.

Gap junction intercellular communication (IC) is thought to be important in chemical carcinogenesis as abnormalities in IC have been found in cancer cells. Perchloroethylene (PERC) is metabolized in rodent liver to dichloroacetic acid (DCA) and trichloroacetic acid (TCA), which are rodent liver carcinogens. Chloral hydrate (CH) and trichloroethanol (TCEth) are kidney metabolites. We used Lucifer yellow scrape-load dye transfer as a measure of IC to look at the effect of PERC, DCA, TCA, CH, and TCEth on Clone 9 cell cultures (normal rat liver cells). Four independent experiments were performed for each chemical using exposure times of 1, 4, 6, 24, 48, and 168 h. Concentrations for each chemical varied and were based on preliminary data on effect and cytotoxicity. To compare the relative effectiveness of each chemical to cause biological change, we identified the lowest concentration and shortest time to significantly reduce dye transfer. DCA caused a significant change at 10 mM at 6 h; TCA, 1 mM at 1 h; CH and TCEth, 1 mM at 24 h; and PERC, 0.01 mM at 48 h. Over a 24-h treatment period, the relative efficiencies, as defined by the concentration needed to produce 50% reduction in IC, were PERC (0.3 mM) >> TCA (3.8 mM) > TCEth (6.6 mM) = CH (7.0 mM) >> DCA (41 mM). Time-course data indicated that PERC, DCA, and TCA produced reduction in IC in a similar fashion, but 5 mM CH or TCEth exhibited variances from these results and may indicate specific cell responses to these chemicals. The mechanism(s) responsible for inhibition of IC by these structurally related chemicals needs to be established.

Analysis of Variance↗
PubMed2005

[Gap junctions--major structures promoting intercellular communication].

Gap junctions provide humoral and electric communication between the cells, thus contributing to their morpho-functional cooperation. Gap junction is formed by multiple intercellular channels, each of them being made by two closed hemichannels--connexons, that are oligomeric transmembrane proteins built by 6 subunits, belonging to connexin family. Permeability and electric conductivity of gap junction channels is determined by molecular peculiarities of connexins, their capacity for phosphorilation and by some extra- and intracellular factors. According to the current data, gap junctions in both cell cultures and tissues are dynamic structures with a short half-life period. Main mechanisms responsible for gap junction assembly and destruction have been discovered. These mechanisms were shown to depend upon peculiarities of differential genome activity and to be controlled by extra- and intracellular factors. The data on the gap junctions in the nervous system, heart and epidermis are presented.

Animals↗