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PubMed2005

Gap junction channels reconstituted in two closely apposed lipid bilayers.

Intercellular communication mediated by gap junction channels plays an important role in many cellular processes. In contrast to other channels, gap junction channels span two plasma membranes resulting in an intracellular location for both ends of the junctional pore and the regulatory sites for channel gating. This configuration presents unique challenges for detailed experimental studies of junctional channel physiology and ligand-activation in situ. Availability of an appropriate model system would significantly facilitate future studies of gap junction channel function and structure. Here we show that the double-membrane channel can be reconstituted in pairs of closely apposed lipid bilayers, as experienced in cells. We have trapped the calcium-sensitive dye, arsenazo III (AIII), partially calcium-saturated (AIII-Ca), in one population of connexin32 reconstituted-liposomes, and EGTA in a second one. In such mixtures, the interaction of EGTA with AIII-Ca was measured by a large color shift from blue to red (decreased absorbance at 652 nm). The exchange of these compounds through gap junctions was proportional to these decrements. Results indicate that these connexon-mediated interliposomal channels are functional and are inhibited by the addition of alpha-glycyrrhetinic acid and by flufenamic acid, two gap junction communication inhibitors. Future use of this model system has the potential to improve our understanding of the permeability and modulation of junctional channels in its native intercellular assembly.

Arsenicals↗
PubMed1998

In vitro and in vivo effects of retrovirus-mediated transfer of the connexin 43 gene in malignant gliomas: consequences for HSVtk/GCV anticancer gene therapy.

In tumors, gap junctional intercellular communication (GJIC) is usually down-regulated and the expression of connexins, membrane proteins constituting gap junction channels, is often low or altered. GJIC, allowing the intercellular diffusion of ganciclovir (GCV) triphosphate, is also one mediator of the 'bystander effect', the phenomenon by which herpes simplex virus thymidine kinase (HSVtk)-transduced, neoplastic cells kill surrounding HSVtk-negative cells when treated with GCV. We set up experiments to evaluate the effects of retrovirus-mediated in vivo gene transfer of connexin 43 in malignancies with low GJIC capacity. We found that U-87 human glioblastoma cells transfected in vitro by the human Cx43 cDNA grow significantly more slowly than control U-87 cells and lose their tumorigenicity when injected subcutaneously in nude mice. When the Cx43 gene was transduced in vitro in U-87 cells by a retroviral producer cell line (N3.2.ii, titer 1.5 x 10(6) c.f.u./ml) in vivo results were similar. However, only when U-87 cells were co-injected with N3.2.ii cells in nude mice in a 1:5 ratio, a 50% reduction in tumor size was obtained during the first 3 weeks. Moreover the coinjection of U-87 cells with N3.2.ii and SBA cells (a retroviral producer cell line expressing the HSVtk gene), was not able to potentiate the effects of GCV administration, suggesting that Cx43 gene transfer requires more efficient vectors to increase the bystander effect in vivo.

Animals↗
PubMed2004

Endocytosis of connexin protein in adrenal cells.

The ability of adrenocorticotropin (ACTH) to affect gap junctions was examined in adrenal cells in vivo and in vitro. Treatment with ACTH increased the size and number of gap junction plaques on the cell membranes in hypophysectomized animals and in adrenal culture. Intracellular (cytoplasmic) annular gap junctions were observed in cells of the inner adrenal cortical zones and in adrenal cell cultures. To investigate the relationship of annular gap junctions to surface junctions, adrenal cells in culture were transfected with cDNA encoding a green fluorescent protein tagged connexin 43 construct (Cx43-GFP), and subsequently studied by time-lapse video microscopy, immunocytochemistry, and transmission electron microscopy (TEM). Internalization of part or all of a surface gap junction plaque resulted in annular gap junction formation. These studies support the hypothesis that cytoplasmic vesicles, initially described with TEM methods, can result from removal of gap junction plaques from the cell surface. It is suggested that hormones can play a regulatory role in cell-cell communication by influencing the availability of gap junction protein at the cell surface and that hormonally-sensitive processes might serve as a means of altering intercellular communication.

Adrenal Glands↗
PubMed2005

Partial cell fusion: a newly recognized type of communication between dedifferentiating cardiomyocytes and fibroblasts.

OBJECTIVE: Fibroblasts have been shown to couple to neonatal cardiomyocytes in heterocellular cultures through functional gap junctions. Our objective was to provide evidence for an additional type of heterocellular communication between fibroblasts and adult cardiomyocytes in vitro and in vivo. METHODS: The contact areas in heterocellular co-cultures were evaluated by specific labeling and the intercellular communication was studied using preloading of fibroblasts with tracer molecules. Heterocellular fibroblast-cardiomyocyte contacts present in the in vitro setting and in the border zone of a rabbit myocardial infarction in vivo were further examined by electron microscopy. RESULTS: Addition of fibroblasts preloaded with the fluorescent low molecular weight tracer calcein-AM to cultured myocytes indicated early dye transfer via connexin 43 functional gap junctions. At a later time-period after co-culturing, dye transfer of fibroblasts preloaded with the high molecular weight tracer dextran 10,000 suggested partial cell fusion. The membrane continuity giving rise to this partial cell fusion was confirmed by electron microscopy, clearly showing areas of intercytoplasmic contacts between fibroblasts and phenotypically adapted (dedifferentiated) cardiomyocytes. Fluorescein-labeled annexin V affinity studies revealed transient exposure of phosphatidylserine at the contact sites, suggesting that phosphatidylserine mediates the fusion process. Close contacts between cardiac fibroblasts and dedifferentiated cardiomyocytes accompanied by disruption of the basal lamina were observed in the border zone of a rabbit myocardial infarction in vivo. CONCLUSION: Our results suggest that the partial cell fusion-type of heterocellular communication in our co-culture model and the contacts observed in vivo may lead to new insights in cardiovascular disease.

Animals↗
PubMed1991

Inhibition of glucose production during hepatic nerve stimulation in regenerating rat liver perfused in situ. Possible involvement of gap junctions in the action of sympathetic nerves.

To explore the possible role of gap junctions in neural regulation of hepatic glucose metabolism, the effects of hepatic nerve stimulation on metabolic and hemodynamic changes were examined in normal and regenerating rat liver which was perfused in situ at constant pressure via the portal vein with a medium containing 5 mM glucose, 2 mM lactate and 0.2 mM pyruvate. 1. The content of connexin 32, a major component of gap junctions in rat liver, decreased transiently to about 25% of the control level in regenerating liver 48-72 h after partial hepatectomy and recovered to normal by the 11th day after the operation. 2. In normal liver, electrical stimulation of the hepatic nerves (10 Hz, 20 V, 2 ms) and infusion of noradrenaline (1 microM) both increased glucose and lactate output and reduced perfusion flow. 3. In early stage of regenerating liver 48 h and 72 h after partial hepatectomy, the increase in glucose output in response to nerve stimulation was almost completely inhibited, whereas the change in lactate balance was partially suppressed and the reduction of flow rate was retained. The response of glucose output to nerve stimulation recovered by the 11th day after partial hepatectomy. In contrast, exogenous application of noradrenaline increased glucose output even in the early stage of regenerating liver. 4. The increase in noradrenaline overflow during hepatic nerve stimulation in the early stage of regenerating liver was approximately the same as in normal liver. Liver glycogen was sufficiently preserved in the early stage of regenerating liver. However, noradrenaline infusion could no more increase glucose output both in normal and in regenerating livers after 24 h of fasting that depleted liver glycogen. These results suggest that the impaired effects of sympathetic nerve stimulation on glucose metabolism observed in regenerating liver are derived neither from reduced release of noradrenaline nor from depletion of liver glycogen, but rather from transient reduction of gap junctions which assist signal propagation of the nerve action through intercellular communication in rat liver.

Animals↗
PubMed1984

Quantitative evaluation of gap junctions in rat brown adipose tissue after cold acclimation.

The decrease in the metabolic capacity of rat brown adipose tissue during the late postnatal period can be reversed by cold acclimation of the animals. In order to find out whether a parallel decrease in capability for intercellular communication observed during this period is also reversed by cold acclimation, gap junction size and number per unit area of cell surface have been quantified in freeze-fracture replicas; cell diameters have been measured in semi-thin sections. It was found that the specific number of gap junctions remains unchanged during cold acclimation. However, the mean gap junction size increases by 75% and the ratio of gap junctional area per cell volume, an index for intercellular exchange capacity, is doubled. This result illustrates further the parallelism between metabolic capacity and cell communication in brown fat.

Acclimatization↗
PubMed1993

Lack of correlation between the gap junctional communication capacity of human colon cancer cell lines and expression of the DCC gene, a homologue of a cell adhesion molecule (N-CAM).

In many human colorectal cancers, the DCC gene encoding for a homologue of the neural cell adhesion molecule (N-CAM) is found to be deleted. Previous work suggested that gap junctional intercellular communication (GJIC) might play an important role in carcinogenesis and could be regulated by the expression of cell adhesion molecules such as E-cadherin in some epithelial cell systems. In order to examine whether the deletion of the putative cell adhesion molecule DCC is related to the level of GJIC, which might, in turn, be important in human colorectal cancers, we compared levels of expression of the DCC gene with the GJIC capacity of a panel of human colorectal adenocarcinoma cell lines isolated from different stages of tumor progression. While the level of GJIC varied between the cell lines studied, we found no correlation between their communication capacity and DCC expression revealed by a reverse-transcriptase/polymerase chain reaction method. This lack of correlation suggests that DCC is not a crucial regulator of GJIC.

Adenocarcinoma↗
PubMed1980

Free calcium in Xenopus embryos measured with ion-selective microelectrodes.

A regulatory role for intracellular free calcium has been suggested in cell division and intercellular communication via gap junctions. Previous measurements of cytoplasmic free Ca2+ during cell division and uncoupling have been made with the Ca2+-sensitive photoprotein aequorin. We now report experiments using Ca2+-sensitive microelectrodes to monitor free Ca2+ in the cells and intercellular fluid of early embryos of the amphibian Xenopus laevis. In addition to measuring basal levels, we have looked for changes in free Ca2+ during cell division and during electrical uncoupling of the normally coupled embryonic cells, induced by acidification of the intracellular medium.

Animals↗
PubMed1999

Expression patterns of gap junctional proteins connexin 32 and 43 suggest new communication compartments in the gastrulating rabbit embryo.

A central problem in embryological research is the identification of mechanisms by which control over the development of a viable individual is maintained. An important role in this process is attributed to intercellular communication the preconditions of which were examined in the present study. Using a range of monoclonal antibodies, the expression patterns of the gap junctional proteins connexin 32 (Cx32) and connexin 43 (Cx43) were examined in whole-mount preparations and cryosections of gastrulating rabbit embryos between 6.0 and 7.5 days post conception. Distinct distribution patterns for Cx32 and Cx43, respectively, were found: Cx32 was exclusively expressed in the hypoblast and yolk sac epithelium (the lower layer of the embryo) whereas Cx43-expression was limited to the epiblast (in the upper layer) and its derivatives. Moreover, the dynamics of the Cx32 and Cx43 expression patterns indicate the existence of smaller tissue compartments within the three embryonic cell layers present at the beginning of gastrulation (epiblast, mesoderm and hypoblast). The most striking one of these smaller compartments is a belt-like area within the lower layer which straddles the epiblast-trophoblast border seen in the upper layer of the embryonic disc. The significance of these compartments for initiating and maintaining the gastrulation process is discussed.

Animals↗
PubMed1988

Effects of SV40 transformation on intercellular gap junctional communication in human fibroblasts.

The effect of SV40 viral transformation of human fibroblasts on intercellular gap junctional communication (IJC) was investigated using a short-term quantitative assay. IJC was measured using metabolic cooperation in a coculture system of argininosuccinate synthetase- and argininosuccinate lyase-deficient human fibroblasts. These cell lines were transformed with origin-defective adenovirus/SV40 recombinant virions, and IJC was determined both between transformed cells (homologous IJC) and between transformed and untransformed cells (heterologous IJC). At equivalent cell densities, homologous IJC between transformed cells was reduced to 25-55% of the level between untransformed cells. Intermediate levels of IJC (50-70% of normal) were observed in heterologous cocultures of transformed with untransformed cells. Transformed and untransformed cells were equally sensitive to inhibition of IJC by phorbol esters and by glycyrrhetinic acid, and also did not differ in the degree of upregulation of IJC by forskolin. We conclude that SV40 transformation of human fibroblasts leads to a partial impairment of IJC which is additive when both communicating partners are transformed.

Cell Communication↗
PubMed1999

Distribution of connexin37, connexin40 and connexin43 in the aorta and coronary artery of several mammals.

Intercellular communication between cells of the vessel wall is established by a combination of diffusion and convection of humoral and endothelial factors in the extracellular fluid or by direct intercellular contacts present in the form of gap junctions composed of proteins called connexins. At least connexin (Cx)37, Cx40 and Cx43 are expressed in the vessel wall, but disparate findings with regard to the cell specific localisation of connexins in the vasculature indicate that the distribution of connexins may be species and vessel specific. Moreover, differences in expression exist between cells in culture and tissue sections. We performed an inventory immunohistochemical study on the localisation of Cx37, Cx40 and Cx43 on tissue sections of the bovine, micropig and rat aorta and coronary system, which represent morphologically and functionally different types of vessels in the arterial system. We could observe Cx40 labelling most commonly, although with various intensities, between endothelial and smooth muscle cells of the species studied, with the exception of rat aortic smooth muscle cells. The distribution of Cx43 is more differentiated and mostly confined to smooth muscle cells, although it can be detected scarcely between endothelial cells. Cx37, when detectable, is predominantly expressed between endothelial cells in a heterogeneous pattern. We conclude that Cx40 is the constitutive vascular gap junction protein in situ and guarantees cell coupling between cells in the vessel wall. The differentiated distribution of both Cx37 and Cx43 suggests they are involved in more dynamic processes.

Animals↗
PubMed1992

Regulation of gap junctional communication in Syrian hamster embryo cells by retinoic acid and 12-O-tetradecanoylphorbol-13-acetate.

Retinoids enhance the frequency of Syrian hamster embryo (SHE) cell colonies with transformed morphology in a similar way to tumor-promoting phorbol esters. The present study shows that retinoids are also potent inhibitors of gap junctional intercellular communication in SHE cells at noncytotoxic concentrations. This is an apparent contrast to the results observed in transformation systems using the mouse cell lines C3H10T1/2 and BALB/c 3T3, where retinoids have been found to reduce the induction of transformation, and also to enhance gap junctional cell communication. Retinoids are thus potent modulators of transformation and cell communication in three transformation systems. For all three cell types, enhancement of communication by retinoids is related to reduced transformation, and inhibition of communication to enhanced induction of transformation. Communication in the SHE cells is completely blocked following 1 h exposure to 30 microM retinoic acid, while concentrations of 0.3-15 microM results in a gradual down-regulation of communication during 1-5 h exposure. Removal of retinoic acid results in complete restoration of communication to control values within a few hours. Primary SHE cells and the cell line BPNi show similar sensitivity for inhibition of communication after exposure to retinoic acid, while BPNi cells are far more sensitive to inhibition of communication by 12-O-tetradecanoylphorbol-13-acetate (TPA) than primary SHE cells. Retinoic acid does not induce inhibition of epidermal growth factor binding, potentiate adenylate cyclase activation or enhance arachidonic acid release, as does TPA, suggesting different mechanisms of action.

Animals↗
PubMed2004

Characteristics of cultured subepithelial fibroblasts in the rat small intestine. II. Localization and functional analysis of endothelin receptors and cell-shape-independent gap junction permeability.

Subepithelial fibroblasts form a cellular network with gap junctions under the epithelium of the gastrointestinal tract. Previously, we have reported their unique characteristics, such as reversible rapid cell-shape changes from a flat to a stellate configuration induced by dBcAMP and endothelins (ETs), and Ca2+ responses to, for example, ETs, ATP, and substance-P. We have now investigated the subtypes of ET receptors both in the rat small intestine and in primary cultured subepithelial fibroblasts isolated from rat duodenal villi. Their properties were compared between wild-type and endothelin-B-receptor-mutant sl/sl rats. Light- and electron-microscopic immunohistochemistry showed intense ETA immunoreactivity in the subepithelial fibroblasts from the small intestine and colon of both wild-type and sl/sl rats. In culture, immunocytochemistry, reverse transcription/polymerase chain reaction analysis, Ca2+ response measurements, and cell-shape change analysis indicated functional ETA and ETB receptors in the wild-type cells, but only ETA in the sl/sl cells. However, wild-type cells were more sensitive to ET-1 than to ET-3 by about one order of magnitude. ETA seemed to be dominant both in vivo and in vitro. The relationship between cell-shape change and gap junction permeability was examined by fluorescence recovery after photobleaching; the gap junctions were usually open but were blocked by carbenoxolone. Permeability did not change significantly with cell-shape change. This network of differentiated subepithelial fibroblasts may maintain intercellular communication via gap junctions to transduce signals evoked in the local network to the whole network. The cell-shape change of the cells through ETA activation may play an important role as a barrier and for intercellular signaling in the intestinal villi.

Animals↗
PubMed1989

Meiotic resumption and gap junction modulation in the cultured rat cumulus-oocyte complex.

Intercellular communication within the ovarian follicle has been implicated in the control of meiotic arrest and maturation in the mammalian oocyte. We have shown that a rapid down-regulation of cumulus cell gap junctions is correlated temporally with meiotic resumption in the intact rat follicle [Larsen et al., Dev Biol, 113:517-521]. Here this relationship has been analyzed further by incubating isolated rat cumulus-oocyte complexes (COCs) with agents known to influence germinal vesicle breakdown (GVBD) or that have been shown to modulate gap junction turnover in vitro. Quantitative freeze-fracture analysis revealed that cumulus cell gap junction membrane decreased significantly prior to the initiation of GVBD in COCs incubated in medium lacking serum or other additives. The addition of serum and follicle-stimulating hormone, an experimental condition that delayed GVBD, accelerated and augmented gap junction loss at both the cumulus cell and oocyte surface. The continuous elevation of cyclic adenosine monophosphate levels, which stimulates gap junction formation in other systems, maintained meiotic arrest but did not interfere with gap junction loss. Conversely, the complete inhibition of junctional loss by a microfilament destabilizing agent, dihydrocytochalasin B, did not alter the course of GVBD normally seen in its absence. Subsequent freeze-fracture analysis and dye coupling experiments confirmed that cumulus and oocyte gap junctions in these preparations were intact and functional during the period of meiotic resumption. These findings suggest that factors other than cumulus and oocyte gap junction turnover are required for the control of meiotic arrest and maturation in the isolated COC. However, these results do support our earlier suggestion that gap junction loss within the cumulus oophorus is instrumental in isolating the oocyte from the regulatory influence of its underlying membrana granulosa cells during meiotic maturation in the intact preovulatory follicle [Larsen et al., Dev Biol, 122:61-71].

Animals↗
PubMed2002

Photolytic flash-induced intercellular calcium waves using caged calcium ionophore in cultured astrocytes from newborn rats.

Waves of elevated intracellular free calcium that propagate between neighboring astrocytes are important for the intercellular communication between astrocytes as well as between neurons and astrocytes. However, the mechanisms responsible for the initiation and propagation of astrocytic calcium waves remain unclear. In this study, intercellular calcium waves were evoked by focal photolysis of a caged calcium ionophore (DMNPE-caged Br A23187) in cultured astrocytes from newborn rats. The focal photolysis of the caged compound resulted in the increase in intracellular calcium in a single astrocyte, and this increase then propagated to neighboring astrocytes. We also analyzed the spatiotemporal characteristics of the intercellular calcium waves, and estimated the propagation pathways for them. The method using a caged calcium ionophore described in this study provides a new in vitro model for the analysis of intercellular calcium waves.

Animals↗
PubMed2002

Cell-to-cell communication in response of E. coli cells at different phases of growth to low-intensity microwaves.

Effects of millimeter waves (MMW) at the frequency of 51.755 GHz were studied in logarithmic and stationary E. coli cells at various cell densities. The changes in the genome conformational state (GCS) were analyzed by the method of anomalous viscosity time dependence (AVTD). Before lysis, the cells were adjusted to the cell density of 4x10(7) cells/ml and all AVTD measurements were run at this cell density. Stationary cells responded to MMW by increase in AVTD, while the same MMW exposure decreased AVTD in logarithmic cells. MMW effects depended on cell density during exposure and were stronger for stationary cells. The observed dependence on cell density suggested a cell-to-cell communication between cells during exposure to microwaves. Decrease in power density (PD) resulted in more striking differences between responses at different cell densities. The data provided evidence that intercellular communication in response to MMW depended on cell status and PD of microwaves. The MMW effects were studied in more detail at low intensity of 10(-17) W/cm(2) in the range of cell densities 4x10(7) to 8x10(8) cells/ml. The obtained sigmoid-like dependence of MMW effect on cell density saturated at approximately 5x10(8) cells/ml. The dependence of MMW effect on cell density was very similar in this study and in previous studies with weak extremely low frequency (ELF) electromagnetic fields (EMF). The data suggested that cell-to-cell communication might be involved in response of cells to weak EMF of various frequency ranges.

Cell Communication↗
PubMed2001

Effect of seeding osteoprogenitor cells as dense clusters on cell growth and differentiation.

One approach for forming tissue equivalents involves seeding of cells into porous scaffolds followed by culture in vitro. Within this paradigm, the strategy by which cells are initially seeded may dictate the ultimate properties of the tissue equivalent. In particular, low cell densities may suffer from poor intercellular communication, whereas high densities may result in an unfavorable microenvironment due to transport limitations. A third alternative is to seed cells as dense clusters, which might benefit from intercellular contact without the high nutrient demand. To test this approach, planar substrates were seeded with 10(4) osteoprogenitor marrow stromal cells either as a diffuse subconfluent dispersion (2.6 x 10(3) cells/cm(2)) or as a single dense cluster (8 x 10(4) cells/cm(2)). In this study, the densely clustered cells demonstrated significantly diminished cell growth and collagen synthesis. However, a significantly higher level of alkaline phosphatase activity--a measure of bone-forming potential--and moderately more mineralization were observed with these dense cultures. These findings show that clustering can enhance the differentiation phase while diminishing the proliferating phase of these diploid cells without requiring large cell numbers. Thus, this seeding strategy may improve the quality of engineered tissues.

Animals↗
PubMed1998

Cell-to-cell communication in differentiation of mycelial fungi.

Electric and ionic interactions in fungal hyphae under controlled environmental conditions were characterized. The interactions were shown to be local and genetically determined. The possibility of their regulation by the blue-violet light and the membrane potential gradient between the adjacent cells was demonstrated. Septal pores providing the intercellular communication in fungi share common functional features with animal gap junctions, plant plasmodesmata, and microplasmodesmata of cyanobacteria. Integration of cells in a structurally and functionally heterogeneous ensemble takes place via local intercellular interactions due to a nonuniform distribution of ionic pumps and secondary transport systems in the apical and proximal hyphal cells. Cell differentiation during the hyphal growth results from the redistribution of functions in apical cells populations. The loss of polarity by growing intercalary hyphal fragments and equalization of ionic gradients during the regeneration of mechanically damaged intrahyphal fragments may indicate the existence of different growth mechanisms in the mycelium. Synchronization of functions of individual hyphal compartments exhibiting considerable electrophysiological heterogeneity takes place during the blue-light signal transduction, which triggers the hyphal differentiation processes.

Carotenoids↗