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PubMed2002

Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure.

OBJECTIVE: Impaired myocyte Ca2+ handling is a common characteristic of failing hearts and increases in calcineurin activity, a Ca2+-sensitive phosphatase, have been implicated in heart failure phenotype. Transgenic mice with cardiac-specific expression of an active form of calcineurin display depressed function, hypertrophy and heart failure. We examined whether defects in cardiomyocyte Ca2+ handling properties contribute to the impaired cardiac function in calcineurin transgenic mice. METHODS: The levels of SR Ca2+ handling proteins, SR Ca2+ transport function and cardiomyocyte mechanics, as well as Ca2+ kinetics were examined in mice overexpressing a constitutively active form of calcineurin. RESULTS: Transgenic expression of activated calcineurin catalytic subunit resulted in significant protein increases (66%) in SERCA2 and decreases (35%) in phospholamban, as well as enhanced (approximately 80%) phospholamban phosphorylation. These alterations in the SR Ca2+-transport proteins resulted in increased V(max) and Ca2+-affinity of SERCA2. The myofibrillar Mg-ATPase activity was also significantly increased at pCa>6.0. The enhanced SR Ca2+ handling and Mg-ATPase activity reflected significant elevation in myocyte contractile parameters (3-fold), Ca2+ transient amplitude (1.5-fold) and the rate of Ca2+ signal decay (2-fold). In contrast, in vivo cardiac function assessed by echocardiography, indicated severely depressed contractility in calcineurin hearts. The apparent disparity in contractile properties between the cellular and multicellular preparations may be partially due to tissue remodeling, including interstitial fibrosis and a marked reduction (45%), dephosphorylation (81%) and redistribution of the gap junctional protein connexin-43, which could compromise intercellular communication. CONCLUSION: Despite enhanced SR Ca2+ handling and contractility in myocytes, pathological remodeling and defects in intercellular coupling may underlie contractile dysfunction of the calcineurin hearts.

Animals↗
PubMed1985

Effects of a teratogen on [3H]uridine nucleotide transfer between human embryonal cells and on gap junctions.

Intercellular communication (IC) mediated by gap junctions (gj) occurs during embryonal development and appears to be important for normal differentiation through the exchange of morphogenetic signalling substances. Disruption of IC by chemicals may induce abnormal development resulting from failed cell-cell interactions. It was established in the present study that genotypically normal human embryonal palate mesenchyme (HEPM) cells displayed IC in cell culture and that the transfer of [3H]uridine nucleotides was inhibited by the potent embryotoxin and teratogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA). IC was mediated by gj which were revealed by freeze-fracture and electron microscopy. Quantitative morphometric analysis showed that inhibition of IC by TPA coincided with a significant reduction in the number of gj. The observations suggest that inhibition of IC by the teratogen TPA may be one among the many mechanisms believed to be responsible for the induction of abnormal development by chemical teratogens.

Cell Communication↗
PubMed2003

Epithelial cells of nasal mucosa express functional gap junctions of connexin 43.

OBJECTIVE: Recent studies have suggested that inositol triphosphate is transmitted through the gap junction of adjacent epithelial cells and communicates the intracellular calcium wave that controls the beating of cilia. Therefore, gap junction-mediated intercellular communication may modulate the metachronal ciliary beating of respiratory mucosa. MATERIAL AND METHODS: The expression and function of gap junctions were evaluated in nasal mucosa using immunofluorescent staining, Western blotting and Lucifer Yellow dye coupling in both whole nasal mucosa and cultured nasal epithelial cells. RESULTS: Among connexins (Cxs) 26, 32 and 43, only Cx43 was found in the nasal mucosa, in both the epithelial cells and submucosa tissue. Using Western blotting, Cx43 protein was found in protein extracts of both whole mucosa and cultured epithelial cells. The Cx43 protein content increased twofold between the 3rd and 6th days of culture. Lucifer Yellow dye, microinjected into single cultured epithelial cells, had spread to the adjacent cells. CONCLUSION: Cx43 is present in nasal mucosa. The expression of Cx43 on epithelial cells increases after culture. The dye-coupling study in epithelial cells indicated that the signal may be transmitted to neighboring cells via a gap junction composed of Cx43. Thus, Cx43 may be involved in the regulation of metachronal ciliary beating in ciliated epithelial cells and growth or differentiation in nasal tissue.

Blotting, Western↗
PubMed2002

Morphology and morphometric investigation of hepatocellular preneoplastic lesions and neoplasms in connexin32-deficient mice.

Gap junctions are composed of protein subunits, called connexins, and provide a pathway for the exchange of ions and small molecules between contacting cells. This transfer of molecules is thought to be an important pathway for direct cell communication, and is involved in tissue homeostasis, growth control and embryonic development. Impairment of gap junctional intercellular communication (GJIC) via different mechanisms may therefore contribute to dysregulated cellular proliferation and subsequent tumor development. We investigated the effect of Connexin32-deficiency on liver histology and the formation of preneoplastic foci and hepatocellular neoplasms in transgenic knockout mice, as Connexin32 (Cx32) is the major gap junction protein in the liver. Loss of Cx32 does not alter the morphology of extrafocal liver tissue. However, after administration of a single dose of diethylnitrosamine (DEN), given 2 weeks after birth, the number and volume fraction of preneoplastic foci showed a 3.3-fold to 12.8-fold increase in the Cx32-deficient mice as compared with the corresponding wildtype groups, regardless of sex and age of the animals. Number and volume fraction of hepatocellular adenomas and carcinomas also increased significantly in these animals. The experimental groups did not differ in the morphology of the different types of preneoplastic foci and neoplasms. On the other hand, Cx32-deficiency without DEN treatment did not lead to an increase in the spontaneous development of any type of preneoplastic hepatic foci or hepatocellular neoplasms in up to 18-month-old Cx32-deficient mice as compared with wildtype controls. In conclusion, our results indicate that impairment of GJIC in mouse liver due to deletion of the Cx32 coding DNA clearly promotes the carcinogenic effect of DEN administration and results in a higher susceptibility to hepatocellular neoplasms, but does not appear to initiate hepatic tumor development.

Animals↗
PubMed1991

Myoendothelial junctions in human brain arterioles.

BACKGROUND: The purpose of this work was to determine whether myoendothelial junctions were present in human brains. SUMMARY OF REPORT: We examined vessels of approximately 30-70 microns i.d. from the brains of five autopsied adult patients. Myoendothelial junctions were found in vessels throughout this range, in both surface arterioles and penetrating arterioles, and were classified into three types. The number of myoendothelial junctions, expressed per unit length of vessels, was five times greater in the smallest than in the largest vessels. Thus, we found 1.62 junctions per millimeter length in arterioles less than 60 microns diameter and 0.31 junctions per millimeter length in arterioles greater than 220 microns diameter. CONCLUSIONS: These findings provide an anatomic basis for communication between endothelial cells and smooth muscle of brain microvessels in humans. The function of this intercellular communication is not yet known; however, findings in animals suggest that endothelium may be required for propagated constriction in brain vessels. The existence of myoendothelial junctions in human brain provides a basis for the hypothesis that propagated constriction depends on transmission of some message or messenger between endothelial cells and muscle.

Arterioles↗
PubMed1992

Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties.

Epidemiological evidence and studies in whole animals and cell culture have indicated that carotenoids have cancer chemopreventive action. In mouse C3H10T1/2 cells, this activity is highly correlated with the ability of carotenoids to up-regulate gap junctional intercellular communication. Here, we report that in mouse cells, carotenoids increase the expression of connexin43, a gene that encodes a major gap junction protein. This effect appears unrelated to their provitamin A or antioxidant properties, since carotenoids with and without provitamin A activity increased levels of connexin43 mRNA and protein, whereas the antioxidants methyl-bixin and alpha-tocopherol were inactive. Moreover, the active carotenoid canthaxanthin did not induce the vitamin A-inducible gene retinoic acid receptor-beta. Connexin43 is the first carotenoid-inducible gene described in mammals. By indicating an additional pathway through which carotenoids function, these data provide a mechanistic basis for cancer chemoprevention by carotenoids and may lead to a re-evaluation of carotenoid physiology.

Animals↗
PubMed2004

Plasmodesmata as a supracellular control network in plants.

The evolution of intercellular communication had an important role in the increasing complexity of both multicellular and supracellular organisms. Plasmodesmata, the intercellular organelles of the plant kingdom, establish an effective pathway for local and long-distance signalling. In higher plants, this pathway involves the trafficking of proteins and various forms of RNA that function non-cell-autonomously to affect developmental programmes.

Cell Communication↗
PubMed1997

An inhibition of gap-junctional communication by cadherins.

The action of Ca(2+)-dependent cell-cell adhesion molecules (cadherins) on cell-to-cell channel-mediated intercellular communication was investigated in mouse L and rat Morris hepatoma cells. These cells fail to adhere to one another in aggregation assays and thus seem to lack cell adhesion molecules. Expression of exogenous cadherin induced strong cell-cell adhesion in both cell types, but had opposite effects of communication, causing inhibition in L cells and improvement in hepatoma cells. Both cells express the connexin43 cell-to-cell channel protein. By western blot we found no cadherin-specific changes in connexin43 protein in either cell type, but connexin43 gap junctional plaque staining, i.e. connexin43 localization to cell-cell junctions, was inhibited in L cells and facilitated in hepatoma cells. In addition we found that the inhibitory effect is largely abolished by blockers of glycosylation. Cadherin-cadherin interactions are known to trigger cell type-specific intracellular signal cascades resulting in diverse end effects, and gap junctional communication/plaque formation seems a further example of such cell type-specificity.

Animals↗
PubMed1987

Effect of in vivo exposure to the liver tumor promoters phenobarbital or DDT on the gap junctions of rat hepatocytes: a quantitative freeze-fracture analysis.

Some effects of in vivo exposure to the liver tumor promoters phenobarbital (PB) and p,p'-dichlorodiphenyltrichloroethane (DDT) on the gap junctions of hepatocytes were examined in a freeze-fracture analysis, using three groups of male ACI rats. Fifteen animals in Group 1 received a basal diet and were killed sequentially at 0, 2, 4, 6 and 8 weeks (three rats at each point) after the start of the experiment. Groups 2 (12 rats) and 3 (12 rats) were given 0.05% PB- and 0.05% DDT-containing diets respectively, and were also killed as Group 1. The frequency of hepatocyte gap junctions (per unit total membrane area) was always greater in PB-treated rats than in control rats at each killing point. In rats given DDT, the frequency of hepatocyte gap junctions was greater than in control rats at 2 and 4 weeks but was less than in control rats at 6 and 8 weeks. The average area of hepatocyte gap junctions in PB- and DDT-treated rats was significantly smaller than that in the corresponding control group (P less than 0.05-0.005). Small gap junctions within the meshwork of tight junctions were apparent only in the animals treated with PB or DDT. Promoter treatment also reduced the proportion of gap junctions per unit of hepatocyte membrane area. Furthermore, in comparison with controls, the size and distribution of gap junctional components were somewhat irregular in promoter-exposed livers. The structural changes in rat hepatocyte gap junctions observed upon in vivo exposure to PB or DDT may suggest an inhibitory effect of these agents on intercellular communication.

Animals↗
PubMed1989

Junctional communication is induced in migrating capillary endothelial cells.

Using an in vitro model in which a confluent monolayer of capillary endothelial cells is mechanically wounded, gap junction-mediated intercellular communication has been studied by loading the cells with the fluorescent dye, Lucifer Yellow. Approximately 40-50% of the cells in a nonwounded confluent monolayer were coupled in groups of four to five cells (basal level). Basal levels of communication were also observed in sparse and preconfluent cultures, but were reduced in postconfluent monolayers. 30 min after wounding, coupling was markedly reduced between cells lining the wound. Communication at the wound was partially reestablished by 2 h, exceeded basal levels after 6 h and reached a maximum after 24 h, at which stage approximately 90% of the cells were coupled in groups of six to seven cells. When the wound had closed (after 8 d), the increase in communication was no longer observed. Induction of wound-associated communication was unaffected by exposure of the cells to the DNA synthesis inhibitor mitomycin C, but was prevented by the protein synthesis inhibitor, cycloheximide. The induction of wound-associated communication was also inhibited when migration was prevented by placing the cells immediately after wounding at 22 degrees C or after exposure to cytochalasin D, suggesting that the increase in communication is dependent on cells migrating into the wound area. In contrast, migration was not prevented when coupling was blocked by exposure of the cells to retinoic acid, although this agent did disrupt the characteristic sheet-like pattern of migration typically seen during endothelial repair. These results suggest that junctional communication may play an important role in wound repair, possibly by coordinating capillary endothelial cell migration.

Adrenal Cortex↗
PubMed2005

New roles for Galpha and RGS proteins: communication continues despite pulling sisters apart.

Large G protein alpha subunits and their attendant regulators of G-protein signaling (RGS) proteins control both intercellular signaling and asymmetric cell divisions by distinct pathways. The classical pathway, found throughout higher eukaryotic organisms, mediates intercellular communication via hormone binding to G-protein-coupled receptors (GPCRs). Recent studies have led to the discovery of GPCR-independent activation of Galpha subunits by the guanine nucleotide exchange factor RIC-8 in both asymmetric cell division and synaptic vesicle priming in metazoan organisms. Protein-protein interactions and protein function in each pathway are driven through the cycle of GTP binding and hydrolysis by the Galpha subunit. This review builds a conceptual framework for understanding RIC-8-mediated pathways by comparison with the mechanism of classical G-protein activation and inhibition in GPCR signaling.

Caenorhabditis elegans Proteins↗
PubMed1995

Functional gap junctions in thymic epithelial cells are formed by connexin 43.

A multiparametric study was carried out to investigate the presence and possible role of communicating junctions in the thymus, particularly in the thymic epithelium, the major component of the thymic microenvironment. The presence of direct cell-cell communication mediated by gap junctions was demonstrated in human and murine thymic epithelial cells (TEC) by means of in situ and in vitro immunohistochemical labeling as well as in vitro fluorochrome injection and double whole-cell patch clamp experiments. Moreover, both immuno- and Northern blot studies revealed that the gap junction protein connexin 43 and its mRNA were present in TEC. Importantly, we showed that thymic endocrine activity, as ascertained by thymulin production, could be specifically down-modulated in vitro by a gap junction inhibitor, octanol. We also investigated the existence of gap junctions between TEC and thymocytes. In thymic nurse cells we were able to detect cell-cell communication, although only a minor percentage of epithelial/thymocyte pairs were coupled in a given moment. In contrast, intercellular communication was not detected between cultured phagocytic cells of the thymic reticulum and the respective rosetting thymocytes. We suggest that gap junctions formed by connexin 43 may represent a novel (and rather cell type-specific) pathway for intrathymic cellular communication, including TEC/TEC as well as possible TEC/thymocyte interactions.

Animals↗
PubMed2004

Histamine reduces gap junctional communication of human tonsil high endothelial cells in culture.

The regulation of gap junctional communication by histamine was studied in primary cultures of human tonsil high endothelial cells (HUTECs). We evaluated intercellular communication, levels, state of phosphorylation, and cellular distribution of gap junction protein subunits, mainly connexin (Cx)43. Histamine induced a time-dependent reduction in dye coupling (Lucifer yellow) associated with reduction in connexin43 localized at cell-cell appositions (immunofluorescence), without changes in levels and phosphorylation state of connexin43 (immunoblots). These effects were prevented with chlorpheniramine, an H1 receptor blocker; indomethacin, a cyclooxygenase blocker; or GF109203X, a protein kinase C inhibitor. Treatment with phorbol myristate acetate, a protein kinase C activator, and 4bromo (4Br)-A23187, a calcium ionophore, mimicked the histamine-induced effects on dye coupling. 8Bromo-cAMP doubled the dye coupling extent and prevented the histamine-induced reduction in incidence of dye coupling. After 24-h histamine treatment, known to desensitize H1 receptors, reapplication of histamine increased cell coupling in a way prevented by ranitidine, an H2 receptor blocker. Thus, activation of H1 and H2 receptors, which increase intracellular levels of free Ca2+ and cAMP, respectively, may affect gap junctional communication in opposite ways. Stabilization of actin filaments with phalloidine diminished but did not totally prevent histamine-induced cell shape changes and reduction in dye coupling. Hence, the histamine-induced reduction in gap junctional communication between HUTEC is mediated by cytoskeleton-dependent and -independent mechanisms and might contribute to modulate endothelial function in lymphoid tissue.

Cells, Cultured↗
PubMed2004

Hierarchy of carcinoma cell responses to apigenin: gap junctional coupling versus proliferation.

We discriminated the role of gap junctional communication and phenotypic constitution of tumour cells in determining their responsiveness to apigenin. Effects of apigenin on intercellular communication and proliferation of two lines of carcinoma cells, uncoupled HeLa cells and their coupled Cx43-transfected counterparts, were analysed and compared with the responses of highly coupled BICR/M1Rk cells. Dye transfer analyses demonstrated that apigenin decreases the degree of coupling in Cx43-coupled populations of HeLa cells but does not affect BICR/M1Rk cells. Similarly, no communication enhancement was observed in originally uncoupled HeLa cell populations. A G2-specific growth arrest paralleled by the induction of apoptosis was observed which was more pronounced and correlated with higher number of apoptotic events in coupled HeLa Cx43 transfectants than in parental cell line. On the other hand, apoptosis was not observed in highly coupled BICR/M1Rk cells, instead, these cells were only transiently blocked in G2 which might be a result of their ability to metabolise apigenin. These data demonstrate a hierarchy of systems determining cellular sensitivity to apigenin. Gap junctional coupling does not influence the quality of cell cycle-related responses to apigenin but modulates their magnitude. This modulating effect of gap junctional coupling depends, however, on a cellular context determined by specific cell phenotype and can be overcome by tissue-specific compensatory mechanisms.

Animals↗
PubMed2004

Gap junction communication between cells aggregated on a cellulose-coated polystyrene: influence of connexin 43 phosphorylation.

The appropriate functioning of tissues and organ systems depends on intercellular communication such as gap junctions formed by connexin (Cx) protein channels between adjacent cells. We have previously shown that Swiss 3T3 cells aggregated on hydrophilic cellulose substratum Cuprophan (CU) establish short linear gap junctions composed of Cx 43 in cell surface plaques. This phenomenon seems to depend on the high intracellular cyclic AMP (cAMP) concentration triggered by attachment of the cells to CU. We have now used a cellulose-coated polystyrene inducing the same cell behaviour to analyse the gap junction communication between aggregated cells. The transfer of the dye Lucifer Yellow (LY) between cells showed that cells aggregated on cellulose substratum rapidly (within 90 min) establish functional gap junctions. Inhibitors of cAMP protein kinase (PKI) or protein kinase C (GF109203X) both inhibited the diffusion of LY between neighbouring cells. Western blot analysis showed that this change in permeability was correlated with a decrease in Cx 43 phosphorylation. Thus, cellulose substrata seem to induce cell-cell communication through Cx 43 phosphorylation modulated by PKA and PKC. To understand the mechanisms by which a substratum regulates gap junctional communication is critically important for the emerging fields of tissue engineering and biohybrid devices.

Animals↗
PubMed1990

Changes in cytosolic CA2+ are not involved in DDT-induced loss of gap junctional communication in WB-F344 cells.

Recent studies have demonstrated that the insecticide DDT is a tumor promoting agent. Similar to many other tumor promoting agents, DDT has been shown to inhibit gap junctional intercellular communication (GJIC) between cells in culture, and it has been suggested that DDT-induced loss of communication between adjacent cells may depend on changes in cytosolic free Ca2+ concentration [( Ca2+]i). In the present study, the role of [Ca2+]i in DDT-induced loss of GJIC was investigated in WB-F344 in rat liver cells using the scrape-loading/dye transfer assay (SLDT) and the Ca2+ fluorescent indicator, fura-2. Our results show that DDT at noncytotoxic concentrations caused a reversible loss of GJIC. Inhibition of GJIC was not associated with detectable increases in [Ca2+]i, and was not prevented by loading cells with the intracellular Ca2+ chelator, BAPTA. In addition, the hydroquinone, tBuBHQ, which caused a 2-3 fold sustained increase in [Ca2+]i, did not inhibit GJIC. Conversely, when untreated cells were loaded with increasing BAPTA concentrations, GJIC were lost. These results indicate that increases in [Ca2+]i are not responsible for DDT-induced loss of communication and that, in general, an increase in [Ca2+]i within physiological levels is not sufficient to abolish GJIC. However, Ca2(+)-dependent processes that are active at normal resting [Ca2+]i appear to be required for the maintenance of GJIC.

Animals↗
PubMed1994

Astrocytic dye coupling in rat hippocampus: topography, developmental onset, and modulation by protein kinase C.

Previous studies have shown that astrocytes constitute a functional syncytium whereas the cytoplasmata of individual cells are connected via gap junctions. Many studies have used cultured astrocytes and have examined electrical coupling with the help of double electrode techniques. Another approach has been the immunohistochemical detection of gap junction proteins in sections of brain tissue. From the results of these experiments it is difficult to infer the extent of astrocytic coupling in situ. To get an impression of the distribution of coupled astrocytes we took advantage of the hippocampal slice preparation which leaves the topography of neurons and astrocytes intact. We performed injections of low molecular weight dyes into single electrophysiologically identified astrocytes. As these dyes can pass through gap junctions this leads to the staining of all connected cells in a certain area, limited by the diffusional spread of the dye. The results show that there is virtually no border to astrocytic coupling between the diverse hippocampal subdivisions. This widespread coupling could already be detected at postnatal day 4, the earliest age tested. Activation of protein kinase C with phorbol esters showed that it is possible to reduce gap junctional communication by some extent. We conclude that although no compartmentalization was seen with respect to astrocytic coupling, the intercellular communication of these glial cells has the capability of being regulated for example by neuronal signals which activate the phospholipase C pathway in astrocytes.

Animals↗
PubMed1993

Transfer of dye among salivary gland cells is not affected by genetic variations of the period clock gene in Drosophila melanogaster.

Larval salivary gland cells of Drosophila melanogaster were injected with a fluorescent dye to assess strengths of intercellular communication among such cells, as influenced by mutations at the period locus and by a per transgene. This clock gene had been reported to increase the extent of dye transfer when mutated such that it shortens the period of biological rhythms; the previous study also showed that a per-null mutant decreased the strength of transfer among salivary gland cells. Our re-examination of this feature of larval physiology--in observer-blind analyses, using the pers and per0 mutants as well as two per-normal strains--revealed no appreciable differences in extents of dye transfer among these four genotypes. These results are discussed in the context of emerging findings which suggest that the period gene's product controls pacemaker functioning as an intracellularly acting entity.

Animals↗