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PubMed1988

Concentration/response effect of 2,2', 4,4', 5,5'-hexabromobiphenyl on cell-cell communication in vitro: assessment by fluorescence redistribution after photobleaching ("FRAP").

Inhibition of gap junction-mediated cell-cell communication might be a mechanism for several types of cellular dysfunctions, including tumor promotion. Although many different assays have been designed to measure gap junction-mediated intercellular communication, we applied a new technique, termed Fluorescence Redistribution After Photobleaching ("FRAP"), to assess the ability of a known tumor promoter, 2,2', 4,4', 5,5'-hexabromobiphenyl (245-HBB), to inhibit cell-cell communication in a concentration-dependent manner. WB-F344 (rat epithelial) cells were plated at low density, exposed to noncytotoxic concentrations of 1, 5, or 20 micrograms 245-HBB/ml medium, and stained with 6-carboxyfluorescein diacetate. Single cells in pairs or clusters of touching cells in each exposure group were examined with FRAP. The results revealed an inverse correlation between the degree of fluorescence redistribution in photobleached cells and the concentration of 245-HBB. Therefore, FRAP appears to be a sensitive and rapid technique for determining complete or partial inhibition of chemically induced intercellular communication in vitro. These results also provide further evidence for the ability of 245-HBB to inhibit gap junction-mediated cell-cell communication in a concentration-dependent manner.

Cell Communication↗
PubMed1985

Effects of calcium on electrical propagation in early embryonic precontractile heart as revealed by multiple-site optical recording of action potentials.

The effects of Ca2+ on electrical propagation in early embryonic precontractile chick hearts were studied optically using a voltage-sensitive merocyanine-rhodanine dye. Spontaneous optical signals, corresponding to action potentials, were recorded simultaneously from 25 separate regions of the eight-to-nine-somite embryonic primitive heart, using a square photodiode array. Electrical propagation was assessed by analyzing the timing of the signals obtained from different regions. Electrical propagation in the heart was suppressed by either lowering or raising extracellular Ca2+. Similar effects were produced by a Ca2+ ionophore (A23187). We have also found that electrical propagation across the primordial fusion line at the midline of the heart was enhanced by increasing, and depressed by lowering, external Ca2+. One possible interpretation is that intercellular communication in the embryonic precontractile heart is regulated by the level of the intracellular Ca2+ concentration, and it is suggested that intercellular communication across the primordial fusion line strongly depends on external Ca2+.

Action Potentials↗
PubMed1992

Cell-cell communication in the embryo of Caenorhabditis elegans.

We have investigated the pattern of cell-cell communication in embryos of the free-living soil nematode Caenorhabditis elegans. For this, we have established a method for microinjection of tracer dyes into individual blastomeres. After iontophoresis of fluorescent dyes of different molecular weights (Lucifer yellow, LY, M(r) 457; rhodamine-labeled dextran, RD, M(r) 4000), we can visualize intercellular communication pathways. The dye-spread of LY, indicating communication via gap junctions, becomes first visible in the late 2-cell stage. From the 4-cell stage onward all cells appear to be well coupled by communication channels, which allow the free diffusion of LY. In contrast, RD remains restricted to the injected cell and its descendants. After the primordial germcell P4 has been generated in the 24-cell stage, dye-spread of LY into this cell and its somatic sister D is delayed. However, the restricted dye-coupling of D is only temporary. After a brief period it joins the somatic compartment. With the beginning of the morphogenesis phase the two existing germline cells (the daughters of P4) are completely uncoupled from the soma, while the latter still forms a single dye-coupling compartment. Only during the second half of embryogenesis different separate somatic communication compartments are established. We followed the pattern of intercellular communication in the alimentary tract and found a progressive restriction into smaller dye-coupling units. Our data are compared to those found in other systems and discussed with respect to cellular determination and differentiation.

Animals↗
PubMed2000

Induction of skin papillomas, carcinomas, and sarcomas in mice in which the connexin 43 gene is heterologously deleted.

It has been suggested that blocked gap junctional intercellular communication plays a crucial part in multistage carcinogenesis. The mouse skin tumor-promoting phorbol esters are potent inhibitors of gap junctional intercellular communication and this inhibition is considered to be a mechanism by which clonal expansion of "initiated" cells is promoted. We examined whether mice in which the gene for a gap junction protein, connexin 43, is heterozygously deleted are more susceptible to chemical carcinogenesis; connexin 43 is expressed in the basal cell layer and the dermis of the skin. When the back skin was painted with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate, the incidence and yields of both papillomas and carcinomas were similar in connexin 43+/- and connexin 43+/+ mice; for this experiment, the original mice with C57BL/6 genetic background was crossed with CD1 strain for three generations. Subcutaneous injection of 7, 12-dimethylbenz[a]anthracene resulted in induction of fibrosarcomas in connexin 43+/- and connexin 43+/+ mice to a similar extent. All papillomas and carcinomas induced with 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate contained the 7,12-dimethylbenz[a] anthracene-specific mutation in the ras gene (A to T transversion at the 61st codon). About 50% of fibrosarcomas also contained this mutation, but in the Ki-ras gene; there was no difference in the prevalence of this mutation in tumors from connexin 43+/- and connexin 43+/+ mice. None of the tumors examined, however, showed any mutation in the connexin 43 gene. These results suggest that the deletion of one allele of the connexin 43 gene does not significantly contribute to, nor alter, the molecular events involved in skin carcinogenesis. These results are compatible with previous observations that nongenetic disruption of function rather than mutations of connexins, commonly occurs in cancer cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Isolated rat hepatocytes can signal to other hepatocytes and bile duct cells by release of nucleotides.

Intercellular communication among certain cell types can occur via ATP secretion, which leads to stimulation of nucleotide receptors on target cells. In epithelial cells, however, intercellular communication is thought to occur instead via gap junctions. Here we examined whether one epithelial cell type, hepatocytes, can also communicate via nucleotide secretion. The effects on cytosolic Ca2+ ([Ca2+]i) of mechanical stimulation, including microinjection, were examined in isolated rat hepatocytes and in isolated bile duct units using confocal fluorescence video microscopy. Mechanical stimulation of a single hepatocyte evoked an increase in [Ca2+]i in the stimulated cell plus an unexpected [Ca2+]i rise in neighboring noncontacting hepatocytes. Perifusion with ATP before mechanical stimulation suppressed the [Ca2+]i increase, but pretreatment with phenylephrine did not. The P2 receptor antagonist suramin inhibited these intercellular [Ca2+]i signals. The ATP/ADPase apyrase reversibly inhibited the [Ca2+]i rise induced by mechanical stimulation, and did not block vasopressin-induced [Ca2+]i signals. Mechanical stimulation of hepatocytes also induced a [Ca2+]i increase in cocultured isolated bile duct units, and this [Ca2+]i increase was inhibited by apyrase as well. Finally, this form of [Ca2+]i signaling could be elicited in the presence of propidium iodide without nuclear labeling by that dye, indicating that this phenomenon does not depend on disruption of the stimulated cell. Thus, mechanical stimulation of isolated hepatocytes, including by microinjection, can evoke [Ca2+]i signals in the stimulated cell as well as in neighboring noncontacting hepatocytes and bile duct epithelia. This signaling is mediated by release of ATP or other nucleotides into the extracellular space. This is an important technical consideration given the widespread use of microinjection techniques for examining mechanisms of signal transduction. Moreover, the evidence provided suggests a novel paracrine signaling pathway for epithelia, which previously were thought to communicate exclusively via gap junctions.

Adenosine Triphosphate↗
PubMed1989

Lack of promoting effect of clonazepam on the development of N-nitrosodiethylamine-initiated hepatocellular tumors in mice is correlated with its inability to inhibit cell-to-cell communication in mouse hepatocytes.

The tumor-promoting ability of clonazepam (CZP), a widely used benzodiazepine anticonvulsant, was investigated in an in vivo mouse liver tumor promotion assay and an in vitro mouse hepatocyte intercellular communication assay. The development of preneoplastic hepatocellular foci of cellular alteration and hepatocellular neoplasms was studied in male B6C3F1 mice initiated, at 5 weeks of age, with a single i.p. injection of N-nitrosodiethylamine (NDEA; 90 mg/kg body weight) in tricaprylin, followed by administration of either phenobarbital (PB; 0.05%) or CZP (0.068% or 0.136%) in diet beginning 2 weeks after carcinogen injection and continuing to 60 weeks of age. Several mice from each group were killed after 9, 21, 33 or 53 weeks on test diet, and portions of liver and other organs were fixed in formalin and examined histologically. Unlike PB, CZP did not promote the development of preneoplastic hepatocellular foci or neoplasms (adenomas and carcinomas) in NDEA-initiated mice. Following limited (2 weeks) dietary exposure at 0.15%, CZP was a potent inducer of hepatic P450IIB1-mediated alkoxyresorufin O-dealkylase activities. In contrast, the degree of induction in hepatic tissue from mice fed 0.136% CZP for 53 weeks was markedly lower than that in mice fed 0.05% PB for 53 weeks. In the in vitro assay, diazepam, a strong tumor promoter in mouse liver, significantly inhibited mouse hepatocyte gap junctional intercellular communication, while CZP had no significant effect on this parameter. Thus, CZP, a drug structurally related to diazepam, is inactive as a liver tumor promoter in mice.

Adenoma↗
PubMed1998

Gap junction channels in the cardiovascular system: pharmacological and physiological modulation.

Intercellular communication provides the basis for the intact functioning of tissue and for various organs and tissue types in an organism to work together. It is the crucial difference between isolated cells and intact tissue. Cells communicate in various ways with each other; these include the release of chemical transmitters, hormones and mediators as well as direct electrical and chemical intercellular communication via gap junction channels. The gap junction coupling is important for the organization of the tissue as an electrical syncytium and for accurate development. Pharmacological modulation of these channels could be important in the fields of arrhythmogenesis, vasomotion and cell differentiation. In this review, Stefan Dhein outlines the structure, synthesis and function of gap junction channels. Since their physiology and pharmacology are best investigated in the cardiovascular system, the second part of the article focuses on the role of gap junctions in the heart and vasculature, with special emphasis on the regulation of the channels by physiological stimuli such as ions, pH mediators and transjunctional voltage as well as their pharmacological modulation.

Animals↗
PubMed2006

Gap junction channel activity in short-term cultured human detrusor myocyte cell pairs: gating and unitary conductances.

Several independent lines of investigation indicate that intercellular communication through gap junctions modulates bladder physiology and, moreover, that altered junctional communication may contribute to detrusor overactivity. However, as far as we are aware, there are still no direct recordings of gap junction-mediated intercellular currents between human or rat detrusor myocytes. Northern and Western blots were used to identify connexin expression in frozen human bladder tissue and short-term cultured human detrusor myocytes. Double whole cell patch (DWCP) recording revealed that human detrusor myocyte cell pairs were well coupled with an average junctional conductance of 6.5 +/- 4.6 nS (ranging from 0.1 to 15 nS, n = 22 cell pairs). Macroscopic gap junction channel currents in human detrusor myocytes exhibited voltage dependence similar to homotypic connexin43. The normalized transjunctional conductance-voltage (G(j)-V(j)) relationship was symmetrical and well described by a two-state Boltzmann relation (G(min) approximately 0.33, V(0) = 63.6 mV, Z = 0.117 or equal to 2.95 gating charges), suggestive of a bilateral voltage-gated mechanism. In symmetric 165 mM CsCl, the measured single-channel slope conductance was approximately 120 pS for the fully open channel and approximately 26 pS for the major substate. Occasionally, other subconductance states were also observed. The single-channel mean open time declined with increasing V(j), accounting for the V(j)-dependent decline of macroscopic junctional current. Qualitatively similar electrophysiological characteristics were observed in DWCP of freshly isolated rat detrusor myocytes. These data confirm and extend previous observations and are consistent with reports in other smooth muscle cells types in which Cx43-mediated intercellular communication has been identified.

Animals↗
PubMed2002

Ciliary neurotrophic factor (CNTF) in combination with its soluble receptor (CNTFRalpha) increases connexin43 expression and suppresses growth of C6 glioma cells.

The loss of gap junctional intercellular communication has been proposedas playing a major role in the process of carcinogenesis. Most neoplastic cells, including C6 gliomas, express less connexins and have fewer gap junctions, reduced gap junctional intercellular communication, and increased growth rates compared with their nonneoplastic counterparts. The purpose of this study was to determine whether ciliary neurotrophic factor (CNTF) can be used to increase endogenous connexin43 levels, increase intercellular coupling, and retard the growth rate of C6 glioma cells. C6 cells were grown in serum-reduced medium (1% serum) and exposed to the following agents: vehicle (PBS), CNTF (20 ng/ml), CNTF soluble receptor (CNTFRalpha; 200 ng/ml), or Complex (CNTF + CNTFRalpha). Reverse transcription-PCR analysis indicated that C6 cells express CNTF mRNA but not CNTFRalpha mRNA. When cells were exposed to the above agents, only Complex caused an up-regulation of connexin43 protein (based on immunocytochemical and immunoblot analysis). Furthermore, Complex increased gap junctional coupling in C6 cells as noted by the passage of the gap junction permeable dye calcein. Finally, it was demonstrated that Complex-treatment reduces the growth rate of C6 cells compared with all of the other agents tested. Taken together, this study has demonstrated that CNTF in combination with its soluble receptor can increase connexin43 expression, increase gap junctional coupling, and reduce the in vitro proliferation of C6 glioma cells.

Animals↗
PubMed2001

Intercellular electrical communication among smooth muscle and endothelial cells in guinea-pig mesenteric arterioles.

1. Current clamp studies using two patch electrodes and morphological observations have been performed in guinea-pig mesenteric arterioles to evaluate intercellular electrical couplings. 2. In electron micrographs, preparations were found to have a single layer of smooth muscle cells. Typical gap junctions were readily observed between endothelial cells only. 3. While immunoreactivity to connexin 40 was strongly expressed on the membranes of endothelial cells only, that to connexin 43 was expressed on both smooth muscle and endothelial cell membranes. 4. Neurobiotin injected into a smooth muscle cell diffused into several neighbouring smooth muscle cells while that injected into an endothelial cell diffused into many endothelial cells. 5. Acetylcholine-induced hyperpolarizations were conducted from endothelial cells to smooth muscle cells with a relative amplitude of 80.1 %. Ba(2+)-induced action potentials were conducted in the opposite direction with a relative amplitude of 92.4 %. 6. An electrotonic potential produced in a smooth muscle cell by current injection diminished steeply with distance as it spread along the muscle layer, plateauing at distances beyond 25 microm. An electrotonic potential produced in an endothelial cell spread within the intima with virtually no reduction. Electrotonic potentials could conduct through myoendothelial couplings, which seemed to behave as ohmic resistors without rectification. 7. The coupling resistance between adjacent smooth muscle cells was estimated to be at least 90 MOhms and that between a smooth muscle cell and the whole endothelial layer to be 0.9 GOhms. 8. The results indicate that although the resistance of myoendothelial couplings is appreciable, the endothelium may be important as a low resistance path connecting many smooth muscle cells.

Animals↗
PubMed1989

Effects of tetradecanoyl phorbol acetate, pyrethroids and DDT in the V79.

The effects of the pyrethroids flucythrinate, cyfluthrin, bioallethrin and resmethrin on metabolic cooperation between V79 cells were investigated. Addition of flucythrinate to cocultures of 6-thioguanine-resistant and 6-thioguanine-sensitive V79 cells significantly increased the mutant cell recovery, indicating inhibition of intercellular communication. No such effect was observed by the other pyrethroids tested. To compare the modes of action of TPA-, DDT-, and pyrethroid-induced inhibition of intercellular communication, co-exposure experiments were undertaken. Addition of TPA, together with increasing doses of fenvalerate or flucythrinate, produced a synergistic response. Various combinations of fenvalerate-, flucythrinate- and DDT-exposure gave results in accordance with an additive response. The result suggest different pathways of action for TPA and the insecticides investigated in this study.

Animals↗
PubMed1987

A co-cultivation system consisting of primary chick embryo hepatocytes and V79 Chinese hamster cells as a model for metabolic cooperation studies.

In this study the role of metabolic cooperation was investigated in a co-cultivation system consisting of primary chick embryo hepatocytes and V79 Chinese hamster cells. A morphological study showed that, in addition to the gap junctions formed between homologous cells, gap junctions were formed also between the primary chick embryo hepatocytes and the V79 Chinese hamster cells. The number of gap junctions present in this system decreased in the following order: hep.-hep., V79-V79, hep.-V79. Under control conditions this number was constant during a co-cultivation period of 48 h. The heterologous gap junctions allowed the passage of 3H-labelled hypoxanthine. Addition of 12-O-tetradecanoylphorbol-13-acetate inhibited this transfer in a dose-related way. Electron microscopical studies with sectioned material showed that inhibition of transfer was paralleled by the disappearance of all gap junctions. There was a remarkable difference between the response time of the different types of gap junctions. Those formed between V79 cells had disappeared after 20 min, whereas those formed between hepatocytes had disappeared after 12 h. The heterologous gap junctions behaved more or less like those between hepatocytes. After exposure times longer than 7 h the transfer of [3H] hypoxanthine was partly restored and morphologically the gap junctions reappeared. When the V79 cells were pretreated with mitomycin C no recovery of intercellular communication was observed, indicating that the adaptation phenomenon is related to the mitotic index of the cells. Dimethylbenzanthracene inhibited the transfer of labelled nucleotides and may be the first example of an indirectly acting inhibitor of intercellular communication.

Animals↗
PubMed2002

Peptides acting at gap junctions.

Gap junction channels are low resistance pathways allowing an action potential to propagate from one cell to the neighboring. Moreover, small molecules (<1000 Da) may pass the channel providing a possibility for metabolic coupling, growth and differentiation control of a cell by its surrounding. Antiarrhythmic peptides can enhance the conductivity of the channels while other peptides, angiotensin or extracellular loop peptides, reduce intercellular communication. On the other hand, peptides like angiotensin II or endothelin-1 can increase expression of certain gap junction channel proteins and, thereby, may affect intercellular coupling chronically. Thus, intercellular communication can be controlled using peptide drugs.

Amino Acid Motifs↗
PubMed1993

Cellular communication in the circadian clock, the suprachiasmatic nucleus.

The hypothalamic suprachiasmatic nucleus functions as the circadian clock in the mammalian brain. Communication between the cells of the suprachiasmatic nucleus is likely to be responsible for the generation and accuracy of this biological clock. Communication between many cells of the brain is mediated by action potentials that pass down the axon and cause release of neurotransmitters at the neuronal synaptic junction. Additional mechanisms of cellular communication appear to operate in the suprachiasmatic nucleus. Several lines of evidence point to multiple modes of cellular communication: these include the continuing operation of the clock after Na(+)-mediated action potentials have been blocked, the orchestrated metabolic rhythms of suprachiasmatic nucleus cells prior to synaptogenesis, the entrainment of fetal to maternal rhythms, and the rapid recovery of function after suprachiasmatic nucleus transplants into arrhythmic rodents. Possible alternative means of intercellular communication in the suprachiasmatic nucleus are examined, including calcium spikes in presynaptic dendrites, ephaptic interaction, paracrine communication, glial mediation, and gap junctions. This paper identifies and examines some of the unanswered questions related to intercellular communication of suprachiasmatic nucleus cells.

Action Potentials↗
PubMed1998

Regulation of connexin43 expression and function by prostaglandin E2 (PGE2) and parathyroid hormone (PTH) in osteoblastic cells.

Connexin43 (Cx43) forms gap junctions that mediate intercellular communication between osteoblasts. We have examined the effects of prostaglandin E2 (PGE2) and parathyroid hormone (PTH) on gap junctional communication in the rat osteogenic sarcoma cells UMR 106-01. Incubation with either PGE2 or PTH rapidly (within 30 min) increased transfer of negatively charged dyes between UMR 106-01 cells. This stimulatory effect lasted for at least 4 h. Both PGE2 and PTH increased steady-state levels of Cx43 mRNA, but only after 2-4 h of incubation. Transfection with a Cx43 gene construct linked to luciferase showed that this effect of PTH was the result of transcriptional upregulation of Cx43 promoter. Stimulation of dye coupling and Cx43 gene transcription were reproduced by forskolin and 8Br-cAMP. Exposure to PGE2 for 30 min increased Cx43 abundance at appositional membranes in UMR 106-01, whereas total Cx43 protein levels increased only after 4-6 h of incubation with either PGE2 or PTH. Inhibition of protein synthesis by cycloheximide did not affect this early stimulation of dye coupling, but it significantly inhibited the sustained effect of PTH and forskolin on cell coupling. In summary, both PTH and PGE2, presumably through cAMP production, enhance gap junctional communication in osteoblastic cell cultures via two mechanisms: initial rapid redistribution of Cx43 to the cell membrane, and later stimulation of Cx43 gene expression. Modulation of intercellular communication represents a novel mechanism by which osteotropic factors regulate the activity of bone forming cells.

Animals↗
PubMed1988

Inhibition of gap junctional blockage by palmitoyl carnitine and TMB-8 in a rat liver epithelial cell line.

Exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to inhibit gap junctional intercellular communication (GJIC) in many cell types in vitro. Using a scrape loading/dye transfer technique, TPA was shown to cause a dose-dependent and transient inhibition of GJIC in WB-F344, a normal rat liver epithelial cell line. Such a down-modulation of intercellular communication was found to be associated with an increase in protein kinase C (PKC) activity. Translocation of this activity to the particulate fraction occurred 10 min after exposure to 16 nM TPA and was consistent with the time course needed to inhibit GJIC. After 6 h exposure to TPA, essentially all the PKC activity was lost concurrent with the recovery of communication in these cells. During this time, the cells also became refractory to inhibition by further addition of TPA. Blockage of communication induced by TPA in WB cells was prevented by treating the cells with 23 microM palmitoyl carnitine for 1 h or 100 microM 8-N, N-(diethylamino)-octyl-3,4, 5-trimethoxybenzoate for 30 min. The results indicate that TPA transiently modulates GJIC in WB cells and PKC activation is possibly involved in blockage of communication in these cells.

Animals↗
PubMed1999

Serial passage of MC3T3-E1 cells alters osteoblastic function and responsiveness to transforming growth factor-beta1 and bone morphogenetic protein-2.

The murine-derived clonal MC3T3-E1 cell is a well-studied osteoblast-like cell line. To understand the effects of serial passages on its cellular function, we examined changes in cell morphology, gap junctional intercellular communication (GJIC), proliferation, and osteoblastic function between early passage (<20) and late passage (>65) cells. MC3T3-E1 cells developed an elongated, spindle shape after multiple passages. Intercellular communication decreased significantly (33%) in late vs. early passage cells. Transforming growth factor-beta1 (TGF-beta1) stimulated cell proliferation in early passage cells and induced c-fos expression, while it inhibited proliferation in late passage cells. Using alkaline phosphatase (ALP) activity and osteocalcin (OC) secretion as markers for osteoblastic function and differentiation, we demonstrated that both markers were significantly reduced after multiple cell passages. Bone morphogenetic protein-2 (BMP-2) significantly enhanced ALP activity and OC secretion in early passage cells while TGF-beta1 exerted an opposite effect. Both BMP-2 and TGF-beta1 had minimal effects on late passage cells. We conclude that serial passage alters MC3T3-E1 cell morphology, and significantly diminishes GJIC, osteoblastic function, TGF-beta1-mediated cell proliferation, and responsiveness to TGF-beta1 and BMP-2. Cell passage numbers should be clearly defined in functional studies involving MC3T3-E1 cells.

3T3 Cells↗