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PubMed1991

Junctional communication of highly and weakly metastatic variant clones from a rat mammary carcinoma in primary and metastatic sites.

We have investigated junctional intercellular communication (JC) in primary and metastatic sites, using two highly and two weakly metastatic variant clones which had been isolated from a rat mammary carcinoma cell line, c-SST-2. After each variant had been subcutaneously inoculated into syngeneic rats, tumor cells were isolated from local tumor (primary tumor) and their metastatic foci (lung, heart and kidney). The cells were then recultured, and we measured their JC in vitro by the dye transfer method with the fluorescent dye Lucifer yellow CH, and found that the homologous (tumor cell-tumor cell) JC of highly metastatic clones were less in recultured tumor cells from primary tumors than that of weakly metastatic clones. At the same time, the heterologous (tumor cell-normal fibroblast) JC of highly metastatic clones was less than that shown by weakly metastatic clones. On the other hand, tumor cells obtained from metastatic foci showed relatively reduced JC (homologous and heterologous) when compared with those from their primary tumors in the weakly metastatic clones. These data suggest that a decrease in and/or a loss of JC may play a role in the expression of metastatic properties.

Animals↗
PubMed2001

Pharmacological evidence for system-dependent involvement of protein kinase C isoenzymes in phorbol ester-suppressed gap junctional communication.

Several phorbol esters are potent activators of protein kinase C. They down-regulate gap junctional intercellular communication and induce phosphorylation of connexin43, but the sensitivity and extent of responses vary much between systems. We asked whether the total protein kinase C enzyme activity or the protein kinase C isoenzyme constitution was of importance for such variations. Some fibroblastic culture systems were compared. It was concluded that the total protein kinase C enzyme activity did not determine the sensitivity to phorbol esters. Furthermore, the use of isotype-specific inhibitors of protein kinase C indicated that protein kinase C alpha, delta, and epsilon may be involved to different extents in different fibroblastic systems in the response to phorbol esters.

Carbazoles↗
PubMed1986

Turing structures in an enzyme-induction system with gap junction-mediated non-linear diffusion.

Two cells, each containing a reaction system modeling genetic induction, are coupled by diffusion. The substrate is moving through gap junctions, the number of which is regulated by the adjacent cells. This leads to a non-linear substrate diffusion term in the rate equations. Stability analysis reveals the conditions for the emergence of stable asymmetric solutions (dissipative structures). Due to non-linear diffusion rigid restrictions on the ratio of the two diffusion constants no longer exist. We demonstrate that substances operating as regulators of intercellular communication and participating in cellular metabolism may exhibit morphogenetic functions.

Animals↗
PubMed2004

The evolution of reproductive restraint through social communication.

The evolution of altruistic behavior through group selection is generally viewed as possible in theory but unlikely in reality, because individual selection favoring selfish strategies should act more rapidly than group selection favoring cooperation. Here we demonstrate the evolution of altruism, in the form of conditional reproductive restraint based on an explicitly social mechanism, modulated by intrapopulation communication comprising signal and evolved response, in a spatially distributed predatory/parasitic/pathogenic model system. The predatory species consistently comes to exploit a signal implying overcrowding, individuals constraining their reproduction in response, with a corresponding increase in equilibrium reproduction rate in the absence of signal. This signaled restraint arises in a robust way for a range of model spatial systems; it outcompetes non-signal-based restraint and is not vulnerable to subversion by noncooperating variants. In these systems, communication is used to evaluate population density and regulate reproduction accordingly, consistent with central ideas of Wynne-Edwards [Wynne-Edwards, V. C. (1962) Animal Dispersion in Relation to Social Behavior (Hafner, New York)], whose claims about the evolutionary importance of group selection helped ignite decades of controversy. This quantitative simulation model shows how the key evolutionary transition from solitary living to sociality can occur. The process described here of cooperation evolving through communication may also help to explain other major evolutionary transitions such as intercellular communication leading to multicellular organisms.

Altruism↗
PubMed1992

Intercellular propagation of calcium waves mediated by inositol trisphosphate.

Two types of calcium (Ca2+) signaling-propagating intercellular Ca2+ waves of increasing intracellular Ca2+ concentration ([Ca2+]i) and nonpropagating oscillations in [Ca2+]i-co-exist in a variety of cell types. To investigate this difference in Ca2+ signaling, airway epithelial cells were loaded with heparin, an inositol 1,4,5-triphosphate (IP3) receptor antagonist, by pulsed, high-frequency electroporation. Heparin inhibited propagation of intercellular Ca2+ waves but not oscillations of [Ca2+]i. In heparin-free cells, Ca2+ waves propagated through cells displaying [Ca2+]i oscillations. Depletion of intracellular Ca2+ pools with the Ca2+-pump inhibitor thapsigargin also inhibited the propagation of Ca2+ waves. These studies demonstrate that the release of Ca2+ by IP3 is necessary for the propagation of intercellular Ca2+ waves and suggest that IP3 moves through gap junctions to communicate intercellular Ca2+ waves.

Calcium↗
PubMed1980

[Physiological importance of gap junctions].

Some structural features of the different types of intercellular junctions which occur in vertebrate tissues (desmosomes, tight and gap junctions, Table 1) are first mentioned. Then, this review is exclusively concerned with gap junctions. The ubiquitous occurrence of these junctions throughout the phylogenetic scale up to man points to a major functional role. Cells of most organized tissues make cell-to-cell channels, 1-2 nm diameter, that provide a structural hydrophilic pathway for free diffusion of inorganic ions and small molecules. Ionic coupling and metabolic cooperation have been shown to be functional expressions of the direct intercellular communication. The role of gap junctions in nonexcitable tissues is not well established (Chap. III). While these junctions are clearly involved in the regulation of some enzymatic activities and exocrine and endocrine secretions, the cell-to-cell transmission of signal molecules necessary for growth control remains largely hypothetical.

Animals↗
PubMed1989

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

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

Animals↗
PubMed1999

Gap junctional communication in cultured human lung carcinoma cells.

Animal tumor models have demonstrated a close correlation between gap junctional, intercellular communication (GJIC) and tumor metastasis. To examine GJIC levels in human lung carcinoma cells, a novel technique was developed: cells were grown on a glass slide, half of which was coated with electrically conductive, optically transparent, indium-tin oxide. An electric pulse which opens transient pores on the plasma membrane was applied in the presence of the fluorescent dye, Lucifer yellow, causing the dye's penetration into the cells growing on the conductive part of the slide. The migration of the dye through gap junctions to the non-electroporated cells growing on the non-conductive area was then observed microscopically under fluorescence illumination. The results show that this is a rapid, precise and highly reproducible assay for GJIC assessment in lines established from lung carcinomas or freshly explanted lung tumor cells. Out of 17 established lines only two had extensive junctional communication, while out of 16 fresh tumor specimens none displayed GJIC. On the other hand, fibroblasts isolated from the same tumors had extensive junctional permeability. The examination of GJIC in a large number of samples could establish a correlation between GJIC and metastasis which might have prognostic value.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Role of Cx43 phosphorylation and MAP kinase activation in EGF induced enhancement of cell communication in human kidney epithelial cells.

Epidermal growth factor (EGF) has been found to induce enhanced gap junctional intercellular communication (GJIC) in the human kidney epithelial cell line K7. This is in contrast to what is reported for other cell types, which all show decreased GJIC in response to EGF. In the present study it is shown that 12-O-tetradecanoylphorbol-13-acetate (TPA) and EGF induce similar phosphorylation pattern of the gap junction protein connexin43 (Cx43) in K7 cells, although their effects on GJIC are opposite. Tyrosine phosphorylation of a 42 kD protein was observed to be induced concomitantly with phosphorylation of Cx43. EGF was however found to induce only serine phosphorylation of Cx43, indicating that the tyrosine kinase activity of the EGF receptor was not directly affecting the gap junction protein. The 42 kD protein phosphorylated on tyrosine was identified to be a mitogen activated protein (MAP) kinase. Both EGF and TPA was found to activate MAP kinase in these cells. Phosphorylation of Cx43 and enhancement of GJIC in response to EGF occurred with difference in time course. Phosphorylation of Cx43 was completed within 15 min, while the enhanced GJIC appeared 2-3 h later. It is therefore possible that regulation of synthesis or transport of Cx43 is responsible for the increase in GJIC, rather than direct involvement of Cx43 phosphorylation. This is in support of our previous finding that protein synthesis is necessary for EGF induced upregulation of GJIC in K7 cells.

Antibodies↗
PubMed2003

Evidence for long-lasting cholinergic control of gap junctional communication between adrenal chromaffin cells.

We investigated long-lasting interactions that may occur between two forms of intercellular signaling: cholinergic synaptic transmission and gap junction-mediated coupling in the rat adrenal medulla. The junctional coupling between chromaffin cells was studied during reduced or blocked synaptic transmission in adrenal slices. First, cholinergic synaptic activity was reduced by pharmacological treatment. Bath-application of the nicotinic receptor antagonists hexamethonium, the oxystilbene derivative F3, or alpha-bungarotoxin, acting at distinct neuronal-like postsynaptic nicotinic acetylcholine receptors (nAChRs), significantly increased the incidence of Lucifer yellow passage (dye coupling) between chromaffin cells (p > 0.7 in treated slices vs p = 0.4 in controls). Dye coupling was associated with an elevated macroscopic conductance of the junctional current measured by dual patch-clamp. Pharmacological inhibition of protein trafficking from the trans-Golgi network to the plasma membrane by either brefeldin A or nocodazole pretreatment prevented the effects of nAChR antagonists on dye coupling. Interestingly, this upregulation of gap junction-mediated coupling in response to reduced synaptic activity is of physiological relevance, because it is found in the newborn rat, in which cholinergic synaptic transmission has not yet matured. This mechanism may also be of importance in pathological conditions, because chronic blockade of synaptic transmission after surgical denervation of the adrenal gland also resulted in increased dye coupling between chromaffin cells. In conclusion, our pharmacological, physiological, and pathological data concur to demonstrate that gap junction-mediated intercellular communication between chromaffin cells undergoes persistent adaptation in response to impairment of synaptic activity. These results strongly suggest that gap junctional communication between chromaffin cells is under tonic inhibitory control exerted by cholinergic synaptic inputs.

Acetylcholine↗
PubMed1996

The cellular Internet: on-line with connexins.

Most cells communicate with their immediate neighbors through the exchange of cytosolic molecules such as ions, second messengers and small metabolites. This activity is made possible by clusters of intercellular channels called gap junctions, which connect adjacent cells. In terms of molecular architecture, intercellular channels consist of two channels, called connexons, which interact to span the plasma membranes of two adjacent cells and directly join the cytoplasm of one cell to another. Connexons are made of structural proteins named connexins, which compose a multigene family. Connexin channels participate in the regulation of signaling between developing and differentiated cell types, and recently there have been some unexpected findings. First, unique ionic- and size-selectivities are determined by each connexin; second, the establishment of intercellular communication is defined by the expression of compatible connexins; third, the discovery of connexin mutations associated with human diseases and the study of knockout mice have illustrated the vital role of cell-cell communication in a diverse array of tissue functions.

Amino Acid Sequence↗
PubMed1990

Differential effects of renal carcinogens and tumor promoters on growth promotion and inhibition of gap junctional communication in two rat renal epithelial cell lines.

To evaluate the effects of renal carcinogens and tumor promoters on gap junctional intercellular communication (IC) and colony formation, two rat kidney epithelial cell lines were examined in vitro. The NRK-52E line was obtained from the American Type Culture Collection and the NK-4 line was established by us from male F344/NCr rats. The NRK-52E line was co-cultured on a confluent monolayer of lethally irradiated NRK-52E cells to determine colony-forming ability (cloning efficiency) and clonal expansion (average surface area of the colonies, SA) and the NK-4 line was cultured on collagen gel. Streptozotocin (STZ), a renal carcinogen, and trisodium nitrilotriacetate monohydrate (NTANa3), a renal carcinogen and tumor promoter, showed mild growth-enhancing effects on both cell lines, as determined by significant increases in SA, but not in cloning efficiency (CE). Sodium barbital (BBNa), a renal tumor promoter, had similar effects, while phenobarbital sodium (PBNa), a non-renal tumor promoter, lacked such activity. The effects of these compounds on gap junctional function were investigated by the Lucifer Yellow dye transfer microinjection assay using monolayers of NRK-52E and NK-4 cells. We found that STZ, NTANa3 and BBNa inhibited IC in NRK-52E cells, in accordance with their reported tumorigenic and/or tumor-promoting activity in vivo, while PBNa did not. Thus, we could present these findings in NRK-52E cells as an in vitro model to examine the potential tissue-specific effects of renal carcinogens and tumor promoters in vitro. We found, however, that other growth control mechanisms beside IC may play a role, because although the NK-4 line did not possess normal IC, the tumor promoters studied had identical growth-promoting effects on colony formation and expansion in both this cell line and the NRK-52E line.

Acetates↗
PubMed2003

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration.

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.

Capillary Permeability↗
PubMed2002

(-)-Epicatechin effects in rat liver epithelial cells: stimulation of gap junctional communication and counteraction of its loss due to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

Gap junctional intercellular communication (GJIC) is a direct signaling pathway for neighboring cells. Disturbances in GJIC are suggested to play a role in carcinogenesis and may be involved in cardiac arrhythmia. Tumor promoters like 12-O-tetradecanoylphorbol-13-acetate (TPA) are capable of inhibiting GJIC, whereas GJIC is stimulated by several micronutrients like genistein, retinoids or carotenoids. (-)-Epicatechin (4-40 microM), a major flavonoid in cocoa and green tea, exhibited stimulatory effects on GJIC in WB-F344 rat liver epithelial cells after 24-72hr of incubation; no change was observed after 90 min. However, treatment of cells for 90 min with TPA (5 or 10nM) led to complete loss of GJIC, whereas 40% loss was found with 1nM. These inhibitory effects of TPA were largely suppressed when (-)-epicatechin or genistein (40 microM) were present during the incubation. In communicating WB-F344 cells, most of the major gap junction protein connexin43 (Cx43) was located in the plasma membrane. When the cells were exposed to TPA, considerably less protein was found in the membrane. Such a delocalization of Cx43 proteins was not observed when TPA was coincubated with the flavonoids, (-)-epicatechin or genistein. It is concluded that TPA affects Cx43 trafficking between cellular compartments, and that this effect is counteracted by (-)-epicatechin or genistein.

Animals↗
PubMed1993

Oleic acid differentially affects gap junction-mediated communication in heart and vascular smooth muscle cells.

The effects of oleic acid (OA) on gap junction-mediated intercellular communication between A7r5 cells and neonatal rat cardiac myocytes were determined. In A7r5 cells the extent of dye coupling was influenced in a biphasic manner by increasing concentrations of OA. Low concentrations of OA (0.1-1 microM) reduced the incidence of dye coupling from 90% (in control cells) to approximately 50%. Further increases in OA concentration, up to 100 microM, had no further effect on extent of dye coupling. In contrast, dye coupling between cardiac myocytes was reduced to near zero levels in a linear fashion by 1-25 microM OA. Whereas high OA concentrations reduce junctional conductance (gj) between heart cells to zero [J. M. Burt, K. D. Massey, and B. N. Minnich. Am. J. Physiol. 260 (Cell Physiol. 29): C439-C448, 1991], gj between A7r5 cells was decreased by a maximum of 45% by OA. These differences in OA sensitivity between the two cell types were not explained by differences in the rate or magnitude of OA uptake by the cells or by differences in the fraction of incorporated OA accessible to albumin washout, i.e., the plasma membrane fraction. Instead, the activity of the individual channel types exhibited different sensitivities to OA. In the presence of increasing concentrations of OA, the activities of first the 70-pS channel population [composed of connexin40 (Cx40)] and then the 108-pS channel population (composed of Cx43) were diminished, leaving predominantly the 140-pS channels (composed of Cx43) at high OA concentrations. The uncoupling effects of OA in both cell types could be reversed by washout with albumin-containing solution; however, higher concentrations of albumin and more vigorous wash conditions were required for full recovery in the A7r5 cells. In addition, albumin also reversed the effects of OA on channel activity. These data suggest that OA binds with greater affinity to the 70- vs. 108- or 140-pS channels and associated with binding is reduced channel activity.

Animals↗
PubMed1996

Increased connexin-43 and gap junctional communication correlate with altered phenotypic characteristics of cells overexpressing the receptor for hyaluronic acid-mediated motility.

Gap junctional intercellular communication (GJIC) and connexin expression are often altered during cell migration, growth, and transformation, each of which is accompanied by cytoskeletal reorganization. Recently, transfection of fibroblast cells with various isoforms of the receptor for hyaluronic acid-mediated motility (RHAMM) was shown to have profound and differential effects on motility, growth, and cell contact behavior as well as on elements of the actin-containing cytoskeleton. These cells thus provide an ideal system in which to investigate parameters implicated in regulation of GJIC as well as expression of connexin-43 (Cx43) in fibroblasts. We used 10T1/2 fibroblast cell lines transfected with RHAMM isoforms or a dominant negative mutated form of RHAMM that blocks the function of endogenous RHAMM. Increased RHAMM expression in the various cell lines was correlated with increased Cx43 and GJIC. These changes were accompanied by a loss of contact inhibition and decreased focal adhesions in all, and elevated motility of most but not all, cell lines tested. RHAMM-induced transformation also resulted in elevated GJIC and Cx43 levels. Reversion to normal growth, motility, and focal adhesion density following transfection of H-ras-transformed fibroblasts with the mutant form of RHAMM was associated with decreases in both Cx43 expression and GJIC. Transfection of 10T1/2 fibroblasts with RHAMM II (exons 5-14) produced altered contact behavior and increased both Cx43 and GJIC but had no effect on motility. All cells expressing high levels of RHAMM, regardless of the isoform, exhibited a lower density of focal adhesions, which corresponds to a reduced organizational state of the cytoskeleton. These results indicate that regulation of GJIC most strongly correlates with altered focal adhesion and cytoskeleton organization that can lead to various secondary responses, including motility, growth, and transformation, and suggest that RHAMM regulates GJIC and Cx43 expression possibly through its actions on focal adhesions and the associated cytoskeleton.

Animals↗
PubMed2001

Cytoplasmic acidification with butyric acid does not alter the ionic conductivity of plasmodesmata.

The effect of lowering cytoplasmic pH on the ionic conductivity of higher-plant plasmodesmata was investigated with corn (Zea mays L. cv. Black Mexican Sweet) suspension culture cells. Exposure to butyric acid decreased the cytoplasmic pH by 0.8 units. Intercellular communication was monitored by electrophysiological techniques that allowed the measurement of membrane resistances of sister cells and the electrical resistance of the plasmodesmata connecting them. The decrease in cytoplasmic pH did not affect the resistance of plasmodesmata, despite the fact that the butyric acid treatment more than doubled the concentration of cytoplasmic calcium. This is discussed in light of previous findings that increases in cytoplasmic calcium increase the electrical resistance of plasmodesmata.

Butyric Acid↗
PubMed2003

The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism.

In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present. Antimycin A caused a modest increase in cytosolic calcium concentration; however, junctional uncoupling still occurred when this rise was prevented. Conditions of ischemic insult (e.g. ischemia or chemical hypoxia) frequently cause the activation of protein kinases, particularly of Src and MAP kinases, and such activations are known to markedly disrupt gap junctional communication. Antimycin-induced junctional uncoupling occurred even in the presence of inhibitors of these kinases. Antimycin A appears able to cause junctional uncoupling either through the ATP depletion it induces as a metabolic poison or via a direct action on gap junction constituents.

Adenosine Triphosphate↗