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PubMed1978

Intercellular junctions in the ciliary epithelium.

The fine structure of the intercellular junctions in the ciliary epithelium of rhesus monkeys and rabbits was studied with conventional electron microscopy of thin-sectioned specimens and the freeze-fracturing technique. In the rhesus monkey, a zonula occludens, zonula adhaerens, gap junctions, and desmosomes interconnect the nonpigmented cells, whereas gap junctions, puncta adhaerentia, and desmosomes connect pigmented to nonpigmented cells, and pigmented cells to one another. In the rabbit, desmosomes are absent between nonpigmented cells, and substituted for by puncta adhaerentia. The zonula occludens between nonpigmented cells greatly varies in its complexity in different regions of the cell perimeter, and in places, it may consist of very few intramembrane strands; this suggests that the ciliary epithelium is relatively leaky to ions and small molecules. Gap junctions are ubiquitous in the ciliary epithelium and particularly numerous at the interface between pigmented and nonpigmented layers; this finding indicates that the cells of the ciliary epithelium are joined in a metabolic syncytium. All gap junctions are characterized by the crystalline configuration which is typical of the uncoupled state; furthermore, in specimens fixed by immersion, they may be caused by uncoupling and take place in the time interval elapsing between interruption of the blood supply and arrival of the fixative fluid. Puncta adhaerentia resemble zonulae adhaerentes in their structural details but are macular in shape instead of encompassing the cell perimeter in a beltlike fashion. In contrast with desmosomes, the intercellular cleft of puncta adhaerentia has an irregular width and contains opaque material, but this never gives rise to the central band typical of desmosomes. On the inner aspect of the junctional membranes, there is a layer of fluffy material but no plaque of insertion for a bundle of tonofilaments. Finally, puncta adhaerentia have no representation in the interior of the plasmalemma and are intimately associated with cytoplasmic microfilaments. They probably anchor to the plasmalemma the contractile apparatus of the ciliary epithelial cells.

Animals↗
PubMed1990

Modification of gap junctional intercellular communication by changes in extracellular pH in Syrian hamster embryo cells.

Studies were conducted to determine the effect of culture medium pH on gap junctional intercellular communication (GJIC) in early passage Syrian hamster embryo (SHE) cells. Previous studies have demonstrated that SHE cells cultured at a clonal density at pH 6.70 are morphologically transformed by carcinogens at a significantly higher frequency than cells cultured in media of higher pH. Several other cell characteristics consistent with promotion-like effects are observed with pH 6.70 culture of SHE cells. It was postulated that the promotion-like effects observed in SHE cells cultured at acidic pH are mediated in part by a reduction of GJIC. In this study, we evaluated GJIC in SHE cells by fluorescent dye coupling. Results from this study indicate that GJIC decreased as a function of decreased extracellular pH. Cells cultured at pH 6.70, 7.15 or 7.35 exhibited 47, 75 and 85% coupled cells respectively. The decrease in dye coupling occurred by 24 h after switching the cells from pH 7.15 to 6.70 medium. The decreased GJIC observed at pH 6.70 was not due to changes in cell proliferation and was reversible within 24 h when pH 6.70 cultures were refed with pH 7.15 medium. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate inhibited SHE cell GJIC in a pH-dependent manner with cells at pH 6.70 exhibiting the greatest inhibition by TPA and cells at pH 7.35 being unresponsive. The effect of pH on GJIC in SHE cells is consistent with the pH-dependent response to chemically induced morphological transformation and may be mechanistically related to this phenomenon.

Animals↗
PubMedDate not supplied

The study of gap junctional intercellular communication in keratinocytes as screening of promoter effect induced by industrial and environmental toxic substances.

BACKGROUND: Disordered functioning of gap junctions between normal and initiated cells has been proposed as one possible mechanism of tumour promotion. Many putative carcinogens such as peroxisome proliferators, are known to activate various signal transduction mechanisms and modulate gap junctional intercellular communication (GJIC). They act as tumour promoters on pre-existing "initiated" cells, rather than as genotoxic initiators. OBJECTIVES: The aim of this article is to provide a screening-tool to evaluate the promoter carcinogen effect of environmental and occupational chemical contaminants, focusing on their ability to alter GJIC. METHODS: GJIC was investigated in serum-free cultured primary human keratinocytes, by directly evaluating the intercellular transfer of a microinjected fluorescent dye (Dye transfer). The expression of caspase 3, which is the ultimate target to be activated of both mitochondrial- and non-mitochondrial-linked pro-apoptotic pathways, was evaluated using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). RESULTS: Mercury chloride (10 nM), mono-methyl Mercury (250 nM) and Trichloroethylene (500 I1M) were shown to significantly inhibit GJIC. Conversely di-methyl mercury, lead acetate and epichloridine had no effect on GJIC. All Trans Retinoic Acid completely reversed the inhibitory effect on GJIC induced by HgCI2 but not that induced by mono-methyl mercury and trichloroethylene. The result of a RT-PCR assay on total RNA cell extract showed that treatment of keratinocytes with 10 nM HgCl2 resulted in a decrease of the pro-apoptotic caspase 3 expression. CONCLUSIONS: In this work a protocol is designed to study gap junction intercellular communication in primary cultures of human keratinocytes which could be used as a reliable screening tool to test the promoter carcinogen effect of various environmental and occupational contaminants.

Air Pollutants, Occupational↗
PubMed1975

The distribution of intercellular junctions in the developing myotomes of the clawed toad.

The distribution of intercellular junctions between premyotomal and myotomal cells of Xenopus embryos has been described. Intermediate junctions, gap junctions, and small desmosomes are found between unsegmented mesoderm cells. In the region of myotome formation gap junctions appear to be absent, although close appositions of cell membranes are found. Both gap and intermediate junctions are numerous between cells of the segmented myotomes; they occur within the myotomes close to the myosepts and at interdigitations between the myotomes across the myosepts. Gap junctions between the myotomes are found in embryos that have hatched and can swim. The observed distribution of gap junctions is correlated with physiological data on electrical coupling. Electrical connections via gap junctions may produce contraction of the axial musculature remote from motor innervation.

Animals↗
PubMed2001

Immunoglobulin and cytokine expression in mixed lymphocyte cultures is reduced by disruption of gap junction intercellular communication.

Connexins (Cx), the protein subunits assembled into gap junction intercellular communication channels, are expressed in primary lymphoid organs and by circulating leukocytes. Human tonsil-derived T and B lymphocytes express Cx40 and 43; circulating human T, B, and NK lymphocytes express Cx43 and directly transfer between each other a low molecular dye indicative that functional gap junctions exist. We now identify specific properties in the immune system underwritten by gap junctions. Mixed lymphocytes cultured in the presence of two reagents with independent inhibitory action on gap junction communication, a connexin mimetic peptide and 18-alpha-glycyrrhetinic acid, markedly reduced the secretion of IgM, IgG, and IgA. The secretion of these immunoglobulins by purified B cells was also reduced by the two classes of gap junction inhibitors. Complex temporal inhibitory effects on the expression of mRNA encoding interleukins, especially IL-10, were also observed. The results indicate that intercellular signaling across gap junctions is an important component of the mechanisms underlying metabolic cooperation in the immune system.

B-Lymphocytes↗
PubMed1985

Intercellular junctions in human tooth-pulp cells in culture in vitro revealed by freeze-fracture, lanthanum impregnation and filipin treatment.

Three kinds of intercellular junctions were detected between human dental pulp cells in explant culture with electron microscopy included filipin detection for cholesterol; desmosome-like junctions observed on ultrathin sections probably contribute to the cohesiveness between cells in culture. Gap junctions, responsible for intercellular communication, exhibited two morphologies on freeze-fracture replicas: a conventional arrangement of their intramembranous particles and a crystalline array corresponding to the formation stage of junctions. Primitive tight junctions were detected on freeze-fracture replicas but not on ultrathin sections. It is likely that they contribute to the cell-to-cell adhesion under culture conditions.

Cells, Cultured↗
PubMed2002

Retinoic acid modulates gap junctional intercellular communication in hepatocytes and hepatoma cells.

Gap junctional communication permits the direct exchange of small molecules and ions and has been implicated in tissue homeostasis/metabolite exchange. The lack of gap junctional intercellular communication (GJIC) plays important roles in the promotion and progression of carcinogenesis. In the present study, we demonstrate that treatment of human hepatoma Hep G2 cells with retinoic acid (RA) results in increased amounts and phosphorylation of connexins, their stabilisation in plasma membrane plaques and enhanced GJIC. In cultured fetal hepatocytes, which represent a non-transformed, proliferating and incompletely differentiated liver system, the effects of RA are limited to the establishment of connexin in areas of cell-cell contact and the improvement of GJIC. This suggests that modulation of cell-cell channel communication by RA occurs differently in these two experimental models: while RA is able to revert cell transformation in Hep G2 cells, in fetal hepatocytes it may induce the expression of a more differentiated phenotype.

Animals↗
PubMed1995

Role of blocked gap junctional intercellular communication in non-genotoxic carcinogenesis.

Gap junctional intercellular communication mediates the transfer of small molecules from the cytoplasm of one cell to that of neighbouring cells. Connexins are the proteins that form the channels responsible for this type of communication. Aberrant expression and function of connexins are often found in cells exposed to tumor-promoting agents and during carcinogenesis, both in cell culture systems and in tissues freshly removed directly from patients and exposed animals. Transfection of connexin genes into tumorigenic cells often exerts negative growth control, suggesting that connexins act as a family of tumor-suppressor genes. Connexin gene mutations appear to be the cause of two human diseases, i.e. X-linked Charcot-Marie-Tooth syndrome and visceroatrial heterotaxia. Connexin genes are therefore important for the maintenance of homeostasis and thus their dysfunction could lead to various forms of disease.

Animals↗
PubMed2002

The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide.

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.

Agaricales↗
PubMed2002

Effects of n-6 and n-3 polyunsaturated fatty acids on gap junctional intercellular communication during spontaneous differentiation of the human colon adenocarcinoma cell line Caco-2.

Gap junctional intercellular communication (GJIC), which modulates cell growth and differentiation, may play an important role in tumor growth. Cancer cells have dysfunctional GJIC, but it is not known whether GJIC is mechanistically involved in the carcinogenic and anti-carcinogenic effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colon tumor cells. Caco-2 cells were used as an in vitro model to study the effects of PUFAs on differentiated as well as undifferentiated human colon cells. The GJIC capacity of this cell line increased during spontaneous differentiation. However, no differential effects between n-6 and n-3 PUFAs on GJIC were observed. Short-term incubation with linoleic acid (18:2n-6), alpha-linolenic acid (18:3n-3), arachidonic acid (AA, 20:4n-6), and eicosapentaenoic acid (EPA, 20:5n-3) did not influence GJIC, while long-term incubation (> 10 days) with linoleic acid and alpha-linolenic acid inhibited GJIC of these colon cells. Long-chain metabolites such as AA and EPA were not formed after incubation with linoleic acid and alpha-linolenic acid, thus excluding the involvement of prostaglandins in the observed effects. Although the exact mechanism of GJIC inhibition is unclear, cytotoxicity probably mediated by lipid peroxidation products seems to be related, because incubation with more PUFAs (AA and EPA) completely abolished GJIC.

Adenocarcinoma↗
PubMed1979

Intercellular junctional specializations in human basal cell carcinoma. A freeze-fracture study.

Intercellular junctions of various types were found on the membrane fracture faces of human nodular basal cell carcinoma (BCC) cells. The junctional types represented include desmosomes, tight junctions, and gap junctions. A semiquantitative comparison of undifferentiated and differentiated nodular BCC showed that gap and tight junctions were observed on all exposed membrane fracture interfaces of the differentiated tumors, while only fifty six per cent of the membrane interfaces of the undifferentiated tumor exhibited similar junctional specializations. These membrane specializations may be a partial reflection of differentiation among the different types of BCC and their contribution to the less invasive character of nodular BCC cannot be ruled out.

Basal Cell Carcinoma↗
PubMed1993

The relationship between wall tension, lamellar thickness, and intercellular junctions in the fetal and adult aorta: its relevance to the pathology of dissecting aneurysm.

It is known that the distribution of stress and strain in the vessel wall is not uniform. We believe that this explains the location of the plane of dissection in dissecting aneurysms of large elastic arteries. We have investigated the effects of non-uniformity of stress and strain on the thickness of each elastic lamella and on the distribution of intercellular junctions in the media of developing and adult rats, to seek evidence to support this hypothesis. Intercellular junctions were identified by transmission electron microscopy of whole wall sections. A morphometric study of elastic tissue distribution was made on an image analysis computer. Differences were analysed using one-way analysis of variance. There are between six and eight elastic lamellae in the aorta of rats. In the fetus, only the internal elastic lamella is complete; the others were not fully formed by term. In the adult, the inner five elastic lamellae were thicker than the remaining two or three, and smooth muscle cells in the thicker lamellar units had more cell-cell contacts of all types examined. These data support the concept of a difference in stress-resisting properties of the aortic wall on the junctions between the inner two-thirds and the outer third of the media. The findings indicate that, as proposed in theoretical models the innermost lamellae support the high tension. In the adult aorta, the structure is modified to enhance the capacity to resist stress in the internal two-thirds of the media.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic Dissection↗
PubMed2003

Role of gap junctional intercellular communication in radiation-induced bystander effects in human fibroblasts.

Involvement of gap junctional intercellular communication (GJIC) in bystander responses of confluent human fibroblasts irradiated with a carbon-ion beam was investigated. It was found that the lower the radiation dose, the higher the yield of radiation-induced micronuclei per nuclear traversal, suggesting the existence of bystander effects. This low-dose sensitivity was increased when GJIC was enhanced by treating cells with 8-Br-cAMP, but it was partly reduced by treating cells with DMSO, an effective scavenger of reactive oxygen species (ROS). Moreover, no low-dose sensitivity was observed when cells were treated with 100 micro M lindane, an inhibitor of GJIC. The survival of irradiated cells was increased by DMSO but was not influenced significantly by cAMP or lindane. On the other hand, G(1)-phase arrest was detected in the irradiated cells, and it was enhanced by cAMP. In contrast, this arrest was reduced or almost eliminated by DMSO or lindane, respectively, even when cells were irradiated with such a high dose that each cell received five nuclear traversals on average. Thus the bystander responses occurred after both low-dose and relatively high-dose irradiation. Our results indicated that both GJIC and ROS contributed to the radiation-induced bystander effect, but gap junctional channels might play an essential role by modulating the release of radiation-induced signaling factors.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1983

Changes in intercellular junctions. I. Embryonic chick liver development.

Quantitation of junctional changes during development may clarify the relation between intercellular junctions and processes such as cell proliferation, morphogenesis, and cytodifferentiation. Chick embryo hepatocytes at 3 days (stage 21) 6 days (stage 28), 14 days (stage 39) of incubation, and 5 days posthatching showed thymidine-labeling indices of 41 +/- 1, 33 +/- 0.8, 13 +/- 0.04, and 7 +/- 1%, respectively. This decline in mitotic activity was correlated with a gradual increase in amount of cell surface occupied by tight junctions. In early embryonic stages these junctions were characteristically linear or macular in form. At embryonic stages 28 and 39 the anastomosing strands of the tight-junction networks characteristically had many free ends while in liver from hatched chicks, tight junction strands frequently ran almost parallel to one another. The area covered by gap junctions increased at embryonic stage 28, then declined with further development. Scanning electron microscopy of developing chick liver showed that the elongated cells of hepatic buds are reorganized into hepatic cords between embryonic stages 21 and 28. Cytochemical demonstration of ATPase at the bile canalicular surface is first apparent at embryonic stage 28 and the cell surface occupied by gap junctions is highest near this time. These findings suggest that modification of proliferative rate or of synthetic activity associated with the maturation of hepatocytes could be correlated with predictable changes in junctional patterns.

Animals↗
PubMedDate not supplied

Retinaldehyde, a potent inhibitor of gap junctional intercellular communication.

Retinaldehyde and retinoic acid are derivatives of vitamin A, and retinaldehyde is the precursor for the synthesis of retinoic acid, a well-known inhibitor of gap junctional intercellular communication. In this investigation, we asked the question if retinaldehyde has similar effects on gap junctions. Gap junctional intercellular communication was measured by scrape-loading and preloading dye-transfer methods, and studies were carried out mainly on cultured liver epithelial cells. Retinaldehyde was found to be a more potent inhibitor (dye transfer reduced by 50% at 2.8 microM) than retinoic acid (dye transfer reduced by 50% at 30 microM) and glycyrrhetinic acid (dye transfer reduced by 50% at 65 microM). Both the 11-cis and all-trans forms of retinaldehyde were equally effective. Retinaldehyde inhibited dye transfer of both anionic Lucifer yellow and cationic Neurobiotin. Inhibition by retinaldehyde developed in less than two minutes at 50 microM, but unlike the reported case with retinoic acid, recovery was slower, though full. In addition to liver epithelial cells, retinaldehyde inhibited gap junctional communication in lens epithelial cells, retinal pigment epithelial cells and retinal ganglion cells.

Animals↗
PubMed2003

Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers.

Glomerular visceral epithelial cells (podocytes) appear to play a central role in maintaining the selective filtration barrier of the renal glomerulus. While the immunoglobulin superfamily member Nephrin was proposed to act as a cell adhesion molecule at the podocyte intercellular junction necessary for maintaining glomerular perm selectivity, the Nephrin ligand has not been identified. The existence of a new subfamily of Nephrin-like molecules including Neph1 was recently described. Genetic deletion of Nephrin or Neph1 resulted in similar phenotypes of podocyte foot process effacement and proteinuria. The subcellular localization of Neph1 and the possibility that Nephrin and Neph1 interact was investigated. Polyclonal antiserum for Neph1 was raised and characterized. Neph1 migrated as a 90-kDa protein on SDS-PAGE under reducing conditions. Neph1 was identified in a glomerular and podocyte-specific distribution in adult rat kidney. Like Nephrin and Podocin, Neph1 was enriched in Triton X-100 detergent-resistant membrane fractions. Consistent with this observation, immunogold electron microscopy demonstrated that Neph1 localized exclusively to lateral margins of podocyte foot processes at the insertion of the slit diaphragm. Neph1 and Nephrin participate in a direct cis-interaction involving their cytoplasmic domains. In addition, interactions between the extracellular domain of Nephrin and itself and between the extracellular domain of Nephrin and that of Neph1 were detected. Neph1 did not interact via a homophilic interaction. These observations suggest that Nephrin and Neph1 form a hetero-oligomeric receptor complex in the plane of the membrane that might interact across the foot process intercellular junction through interactions between Nephrin with itself and Neph1.

Animals↗
PubMed1968

Electrophysiological evidence for low-resistance intercellular junctions in the early chick embryo.

Electrophysiological evidence is presented for the exchange of small ions directly between cells interiors, i.e. "electrical coupling," in the early chick embryo. Experiments with intracellular marking show that coupling is widespread, occurring between cells in the same tissue, e.g. ectoderm, notochord, neural plate, mesoderm, and Hensen's node, and between cells in different tissues, e.g. notochord to neural plate, notochord to neural tube, notochord to mesoderm. The coupling demonstrates the presence of specialized low-resistance intercellular junctions as found in other embryos and numerous adult tissues. The results are discussed in relation to recent electron microscopical studies of intercellular junctions in the early chick embryo. The function of the electrical coupling in embryogenesis remains unknown, but some possibilities are considered.

Animals↗
PubMed1998

Intercellular junctional maturation in the stria vascularis: possible association with onset and rise of endocochlear potential.

The postnatal maturation of intercellular junctions of marginal and basal cells of the stria vascularis was examined in the gerbil using thin sections and freeze fracture techniques. Immunohistochemical methods were used to determine the presence of Na,K-ATPase postnatally. The onset and growth of endocochlear potential (EP) was also measured. In marginal cells, the apical surface and junctional region around the apical pole of the cell was found to have adult-like characteristics by the time of onset of EP, whilst the increase in staining for Na.K-ATPase temporally coincided with an increasing density of intra-membrane protein particles on the infoldings of marginal cell lateral membranes. Maturation of the junctional specialisations of the basal cells was found to correspond temporally with the period of onset and rise of EP. Tight junctions between basal cells first appeared as small, broken strands composed of widely spaced particles at 6 days after birth (DAB). These junctional strands increased in number and in particle density until adult-like at 16 DAB when they covered large areas of the basal cell lateral membrane. Gap junctions on the apical membrane of basal cells first appeared as small patches of loosely packed junctional elements at 6 DAB. Between 8 and 16 DAB the area of membrane occupied by the gap junctions increased, reaching a mature conformation by 18 DAB. The results suggest that EP maturation is dependent upon the development of sealing between the basal cells by tight junctions and also the establishment and development of gap junctions in the apical plasma membrane of basal cells, associated with intermediate cells.

Age Factors↗