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At least 1,207 records · Page 67Linked to original sources
PubMed2004

Chronic regulation of the expression of gap junction proteins connexin40, connexin43, and connexin45 in neonatal rat cardiomyocytes.

Gap junction channels form the basis of intercellular communication in the heart. In the working myocardium, the connexin43 (Cx43) is most abundantly found, whereas connexin40 (Cx40) is expressed in the atria and in the conduction system [together with low levels of connexin45 (Cx45)]. However, little is known about the differential regulation of the connexins by pathophysiologically stimuli such as tumor necrosis factor alpha (TNFalpha). Inasmuch as TNFalpha may play a contributory role in the concert of factors involved in the pathophysiology of heart failure and because this cardiac disease often leads to ventricular reentrant arrhythmia, the goal of our study was to find out whether TNFalpha may influence the expression of the cardiac connexins connexin43, connexin40, and connexin45. Neonatal rat cardiomyocytes were exposed to TNFalpha (10, 40, 100, 400, and 1000 pg/ml) for 24 h with or without additional treatment with the mitogenic-activated protein kinase (MAP-kinase) inhibitors SB203580 [4-(4-fluorophenyl)-2-(4-methyl-sulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; 10(-5) M, protein38 mitogenic-activated protein kinase (p38 MAP kinase) inhibitor] or the MEK1 (mitogenic-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 10(-5) M]. Connexin43, connexin40, and connexin45 expressions were analysed using Western blot analysis, immunohistology, and polymerase chain reaction (PCR) studies (connexin43 and connexin40). TNFalpha induced a concentration-dependent increase in connexin43 (by 2.9+/-0.6, P<0.05, n=5) but not in connexin40 or connexin45 expressions. Both connexins (40 and 45) showed a very low expression near the detection limit. The increases in connexin43 expression could be completely suppressed by SB203580 (0.9+/-0.4, P<0.05, n=5) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect connexin43 content. Additional PCR experiments revealed increases in connexin43 mRNA under the influence of 100 pg/ml TNFalpha (211+/-38%, P<0.05, n=5), which could be completely suppressed by SB203580. In contrast, the connexin40 expression remained unchanged. From these results, we conclude that TNFalpha can differentially regulate cardiac connexin expression via p38 MAP kinase pathway and thus may alter intercellular communication. This may contribute to the changes observed in heart failure with regard to the formation of an arrhythmogenic substrate.

Animals↗
PubMed1998

Acute inhibition of spontaneous uterine contractions by an estrogenic polychlorinated biphenyl is associated with disruption of gap junctional communication.

An estrogenic polychlorinated biphenyl, 4-hydroxy-2',4', 6'-trichlorobiphenyl (4-OH-TCB), inhibits oscillatory uterine contractions immediately. Because increased gap junction formation is associated with the development of synchronized uterine contractions at term, we examined whether the inhibitory effect of 4-OH-TCB on spontaneous oscillatory contractions was due to the disruption of gap junctional communication. The effect of 4-OH-TCB on gap junctional communication was determined by intercellular Lucifer yellow dye transfer in primary cultures of myometrial myocytes isolated from midgestation rats. Intercellular dye transfer was inhibited by 4-OH-TCB or 17beta-estradiol in a concentration-dependent manner. The inhibitory effect of 4-OH-TCB on intercellular dye transfer was reversed by tetraethylammonium (TEA). To examine effects on uterine contraction, longitudinal uterine strips were excised from midgestation rats and placed in muscle baths for isometric force measurement. Spontaneous uterine oscillation was suppressed by 4-OH-TCB or 17beta-estradiol. The inhibitory effects of 4-OH-TCB and 17beta-estradiol on spontaneous oscillations were counteracted by TEA but were not affected by a calcium ionophore (A23187) or a calcium-dependent potassium channel blocker (apamin). These results suggest that the acute inhibition of spontaneous oscillatory contractions by an estrogenic polychlorinated biphenyl may result from the disruption of intercellular communication.

Animals↗
PubMed1984

The regulation of hypoxanthine guanine phosphoribosyl transferase activity through transfer of PRPP by metabolic cooperation.

We have developed a method of relating changes in hypoxanthine guanine phosphoribosyl transferase (HGPRTase) activity to the rate of phosphoribosyl pyrophosphate (PRPP) synthesis in isolated cell lines and in co-cultures of different cell lines. Using this approach, we have determined the response of the HGPRTase activity of communication-competent and communication-incompetent cells to changes in PRPP content. The HGPRTase activity of HGPRT+ communication-competent NS cells responds to changes of their own PRPP level, as well as to changes of the PRPP level of HGPRT- cells with which they are co-cultured. In contrast, the HGPRTase activity of the HGPRT+, but communication-incompetent L929 cells responds to changes of their own PRPP content but not to changes of the PRPP content of the cocultured HGPRT- cells. These and other experiments show that PRPP is freely exchangeable between communication-competent cells and that the intracellular activity of HGPRTase in one cell can be regulated by changes in the levels of its substrate in another cell through metabolic cooperation. The results also indicate that HGPRTase normally functions at a small fraction of its total activity, and that this can be greatly increased by raising the intracellular PRPP levels. Furthermore, it is found that when communication-competent cells establish intercellular communication, they share a common pool of PRPP and of purine nucleotides. This approach can be used as the basis of a biochemical method for the quantitation of metabolic cooperation between cells.

Adenine↗
PubMed2004

What is the importance of the immunological synapse?

The immunological synapse (IS) has proved to be a stimulating concept, particularly in provoking discussion on the similarity of intercellular communication controlling disparate biological processes. Recent studies have clarified some of the underlying molecular mechanisms and functions of the IS. For both T cells and natural killer (NK) cells, assembly of the IS can be described in stages with distinct cytoskeletal requirements. Functions of the IS vary with circumstance and include directing secretion and integrating positive and negative signals to determine the extent of response.

Animals↗
PubMed2005

Protein phosphatase modulation of the intercellular junctional communication: importance in cardiac myocytes.

The rhythmic contraction of a four-chambered heart is a highly co-ordinated process, requiring the sequential activation of pacemaker cells and the propagation of activity throughout the whole myocardium. Gap-junctional channels, providing enclosed conduits for direct cell-to-cell transfer of ions and small molecules between adjacent cells, allow depolarising currents to flow from excited to non-excited regions of the network and a gradual spreading of the action potential. Gap-junctional channels are dodecamers of transmembrane proteins belonging in chordates to the connexin (Cx) family. In mammalian hearts, cardiomyocytes most prominently express junctional channels built of three Cxs: Cx40, Cx43 and Cx45. As with the great majority of Cx, they are phosphoproteins and exist under different phosphorylated levels. Phosphorylation, a widespread post-translational modification of proteins, is a primary means of mediating signal transduction events that control numerous cellular processes via a highly regulated dynamic interplay of protein kinases (PKs) and protein phosphatases (PPs). These processes appear implicated in the regulation of gap-junctional communication at several stages of the Cx lifecycle, including intracellular Cx trafficking, connexon assembly and disassembly, Cx degradation as well as the gating of gap-junction channels, but the underlying mechanisms remain poorly understood. Although PKs have an established role in this process, less is known about the involvement of PPs. The present review examines the roles played by protein dephosphorylation catalysers in the regulation of the gap-junctional communication in general, with a special focus on the junctional communication between cardiac cells.

Alkaline Phosphatase↗
PubMed1988

Intercellular communication-filling in the gaps.

Coordination and synchrony of a variety of cellular activities in tissues of plants and animals occur as a consequence of the transfer of low molecular weight biosynthetic and signaling molecules through specialized structures (plasmodesmata in plant cells and gap junctions in mammalian cells) that form aqueous channels between contacting cells. Investigations with rat liver demonstrated that cell-cell communication is mediated by a 32 kilodalton polypeptide that forms a hexameric pore structure in the plasma membrane. Following association with the same structure in a contiguous cell, a trans-double membrane channel is created that has been termed a gap junction. In plant tissue, long tubelike structures called plasmodesmata are suggested to serve a similar cell-cell linking function between cytoplasmic compartments. Although morphologically distinct, dynamic observations suggest similarities in transport properties between gap junctions and plasmodesmata. Recent work now provides evidence that these functional similarities may reflect a more profound identity between the paradigm animal gap junction polypeptide (32 kilodalton rat liver polypeptide) and an immunologically homologous protein localized to plant plasma membrane/cell wall fractions that may be a component of plasmodesmata.

Journal Article↗
PubMed1994

A model for the propagation of intercellular calcium waves.

In response to mechanical stimulation of a single cell, intercellular Ca2+ waves propagate through airway epithelial and glial cell cultures, providing a mechanism for intercellular communication. Experiments indicate that intercellular propagation of the Ca2+ wave is mediated by the movement of inositol 1,4,5-trisphosphate (IP3) through gap junctions. To explore the validity of this hypothesis, we have constructed and solved a system of partial differential equations that models the Ca2+ changes induced by the movement of IP3 between cells. The model is in good qualitative agreement with experimental data, including the behavior of the wave in the absence of extracellular Ca2+, the shape of the subsequent asynchronous Ca2+ oscillations, and the passage of a wave through a cell exhibiting Ca2+ oscillations. However, the concentration of IP3 that is required in each cell to propagate the wave may not be achieved by passive diffusion of IP3 through gap junctions from the stimulated cell. We therefore suggest that Ca(2+)-independent regenerative production of IP3 might be necessary for the propagation of intercellular Ca2+ waves.

Animals↗
PubMed2001

Gap junction assembly: multiple connexin fluorophores identify complex trafficking pathways.

The assembly of gap junction channels was studied using mammalian cells expressing connexin (Cx) 26, 32 and 43 in which the carboxyl terminus was fused to green, yellow or cyan fluorescent proteins (GFP, YFP, CFP). Intracellular targeting of Cx32-CFP and 43-GFP to gap junctions was disrupted by brefeldin A treatment and resulted in a severe loss of gap junctional intercellular communication reflected by low intercellular dye transfer. Cells expressing Cx43-GFP exposed to nocodazole showed normal targeting to gap junctions and dye transfer. Cx32 and 43 thus appear to be transported and assembled into gap junctions via the classical secretory pathway. In contrast, we found that assembly of Cx26-GFP into functional gap junctions was relatively unaffected by treatment of cells with brefeldin A, but was extremely sensitive to nocodazole treatment. Coexpression of Cx26-YFP and Cx32-CFP indicated a different intracellular distribution that was accentuated in the presence of brefeldin A, with the gap junctions in these cells constructed predominantly of Cx26-YFP. A site specific mutation in the first transmembrane domain that distinguished Cx32 from Cx26 (Cx32128L) resulted in the adoption of the trafficking properties of Cx26 as well as its unusual post-translational membrane integration characteristics. The results indicate that multiple intracellular connexin trafficking routes exist and provide a further mechanism for regulating the connexin composition of gap junctions and thus specificity in intercellular signalling.

Animals↗
PubMed1994

[Oncology, pathology and companion animal practice].

A review of research in veterinary oncology, as executed in Amsterdam and Utrecht, is presented. Also an inquiry into the cooperation between oncologist, pathologist and practitioner is discussed. It is concluded that microscopic tumour diagnosis is practized at too low a scale (+/- 30%). Veterinary oncology has significance both from the veterinary and the comparative (model) point of view. Etiologic-pathogenetic and biologic-therapeutic aspects are studied in a multidisciplinary way. Intercellular communication, growth factors and intercellular matrix are items of present and future research. Molecular-genetic research is in progress. Prevention of mammary tumours by ovariectomy (dog, cat) and of malignant lymphoma (cat) by fighting FeLV seems promising.

Animals↗
PubMed1997

How do injured cells communicate with the surviving cell monolayer?

Mechanically scratching cell monolayers relieves contact inhibition and induces surviving cells near the wound edge to move and proliferate. The present work was designed to test whether surviving cells passively respond to newly available space, or whether cells are actively stimulated by signals from injured cells nearby. We monitored intracellular free Ca2+ ([Ca2+]i) while scratching confluent monolayers of bovine pulmonary endothelial cells and mouse mammary epithelial cells. Within seconds after wounding, a transient elevation of [Ca2+]i was observed in surviving cells. In endothelial cells, the [Ca2+]i elevation propagated into the monolayer for a distance of 10 to 12 cell rows at a speed of 20 to 28 microm/second. The amplitude of the wave of [Ca2+]i was reduced as it propagated into the monolayer, but the velocity of the wave was nearly constant. Cells that experienced the [Ca2+]i elevation had intact plasma membranes, and survived for over 24 hours post wounding. Removing extracellular Ca2+ decreased the amplitude by two-thirds and reduced the propagation rate by half, suggesting that Ca2+ influx contributed to the increased [Ca2+]i. To determine how [Ca2+]i waves were stimulated, we blocked extracellular communication by fluid perfusion or intercellular communication by breaks in the monolayer. In bovine pulmonary artery endothelial cultures, the [Ca2+]i wave passed over breaks in the monolayer, and was prevented from traveling upstream in a perfusion chamber. Conditioned media from injured cells also elevated [Ca2+]i in unwounded reporter cultures. In mouse mammary epithelial monolayers with established cell-cell contacts, the [Ca2+]i wave passed over breaks in the monolayer, but was only partially prevented from traveling upstream during perfusion. These experiments showed that mechanical wounds lead to long distance, [Ca2+]i-dependent communication between the injured cells and the surviving cell monolayer through at least two mechanisms: first, extracellular release of a chemical stimulus from wounded cells that diffused to neighboring cells (present in both monolayers); second, transmission of an intercellular signal through cell-cell junctions (present in the mammary epithelial monolayers). Thus, mechanical injury provided a direct, chemical stimulus to nearby cells which have not themselves been damaged.

Animals↗
PubMed2002

The functional expression of connexin 43 in articular chondrocytes is increased by interleukin 1beta: evidence for a Ca2+-dependent mechanism.

Cell-to-cell interactions and gap junctions-dependent communication are crucially involved in chondrogenic differentiation, while in adult articular cartilage direct intercellular communication occurs mainly among chondrocytes facing the outer cartilage layer. Chondrocytes extracted from adult articular cartilage and grown in primary culture express connexin 43 and form functional gap junctions capable of sustaining the propagation of intercellular Ca2+ waves. Degradation of articular cartilage is a characteristic feature of arthritic diseases and is associated to increased levels of interleukin-1 (IL-1) in the synovial fluid. We have examined the effects of IL-1 on gap junctional communication in cultured rabbit articular chondrocytes. Incubation with IL-1 potentiated the transmission of intercellular Ca2+ waves and the intercellular transfer of Lucifer yellow. The stimulatory effect was accompanied by a dose-dependent increase in the expression of connexin 43 and by an enhanced connexin 43 immunostaining at sites of cell-to-cell contact. IL-1 stimulation induced a dose-dependent increase of cytosolic Ca2+ and activates protein tyrosine phosphorylation. IL-1-dependent up-regulation of connexin 43 could be prevented by intracellular Ca2+ chelation, but not by inhibitors of protein tyrosine kinases, suggesting a crucial role of cytosolic Ca2+ in regulating the expression of connexin 43. IL-1 is one of the most potent cytokines that promotes cartilage catabolism: its modulation of intercellular communication represents a novel mechanism by which proinflammatory mediators regulate the activity of cartilage cells.

Animals↗
PubMed2000

Interleukin-1beta increases the functional expression of connexin 43 in articular chondrocytes: evidence for a Ca2+-dependent mechanism.

Cell-to-cell interactions and gap junctions-dependent communication are crucially involved in chondrogenic differentiation, whereas in adult articular cartilage direct intercellular communication occurs mainly among chondrocytes facing the outer cartilage layer. Chondrocytes extracted from adult articular cartilage and grown in primary culture express connexin 43 (Cx43) and form functional gap junctions capable of sustaining the propagation of intercellular Ca2+ waves. Degradation of articular cartilage is a characteristic feature of arthritic diseases and is associated to increased levels of Interleukin-1 (IL-1) in the synovial fluid. We have examined the effects of IL-1 on gap junctional communication in cultured rabbit articular chondrocytes. Incubation with IL-1 potentiated the transmission of intercellular Ca2+ waves and the intercellular transfer of Lucifer yellow. The stimulatory effect was accompanied by a dose-dependent increase in the expression of Cx43 and by an enhanced Cx43 immunostaining at sites of cell-to-cell contact. IL-1 stimulation induced a dose-dependent increase of cytosolic Ca2+ and activates protein tyrosine phosphorylation. IL-1-dependent up-regulation of Cx43 could be prevented by intracellular Ca2+ chelation but not by inhibitors of protein tyrosine kinases, suggesting a crucial role of cytosolic Ca2+ in regulating the expression of Cx43. IL-1 is one of the most potent cytokines that promotes cartilage catabolism; its modulation of intercellular communication represents a novel mechanism by which proinflammatory mediators regulate the activity of cartilage cells.

Animals↗
PubMed2004

Role of glycosaminoglycans in cellular communication.

Glycosaminoglycans are of critical importance in intercellular communication in organisms. This ubiquitous class of linear polyanions interacts with a wide variety of proteins, including growth factors and chemokines, which regulate important physiological processes. The presence of glycosaminoglycans on cell membranes and in the extracellular matrix also has resulted in their exploitation by infectious pathogens to gain access and entry into animal cells. This Account examines the structural and physical characteristics of these molecules responsible for their interaction with proteins important in cell-cell communication.

Animals↗
PubMed2001

The role of connexin-mediated cell-cell communication in breast cancer metastasis.

Gap junctional intercellular communication (GJIC) is a form of cell-cell communication mediating the exchange of small molecules between neighboring cells. Gap junctions (GJs) are formed by connexins (Cxs), and are subject to tight and dynamic regulation. They are involved in the cell cycle, differentiation, and cell signaling. The loss of Cxs and GJs is a hallmark of carcinogenesis, while their induction in cancer cells leads to a reversal of the cancer phenotype, induction of differentiation, and regulation of cell growth. On the basis of the observations about Cx loss in breast cancer, this review examines Cxs' involvement in breast cancer metastasis. Previous work indicates that Cx expression is inversely correlated to metastatic potential. This is probably because of the loss of cooperation between neighboring cells, leading to cell heterogeneity and cell dissociation in the tumor. The possible involvement of Cx activity during metastasis will be discussed.

Breast Neoplasms↗
PubMed2000

[Intra- and intercellular Ca(2+)-signal transduction].

Calcium is one of the most universal signal-transduction elements in a large variety of cells ranging from bacteria to specialized neurons. Ca2+ acts as a second messenger controlling such processes as secretion, cell differentiation or signal transmission. In order to be able to execute their specific functions and to react in a coordinated way to stimuli, multicellular organs need a precise orchestration of cellular functions. For this purpose cells have developed different forms of intercellular communication (IC). In this study we investigated a number of mechanisms of intracellular propagation and IC using experiments with fluorescent Ca(2+)-indicators, confocal microscopy and digital imaging techniques. In ROS 17/2.8 osteoblasts, retinal pigment epithelial cells (RPE) and CPAE endothelial cells, a small mechanical deformation of the plasma membrane results in a transient increase of free cytoplasmic Ca2+ concentration ([Ca2+]i). This Ca(2+)-rise starts at the site of stimulation and propagates concentrically to neighboring cell layers. The intracellular Ca(2+)-wave in RPE and ROS cells is caused by Ca(2+)-influx followed by Ca(2+)-release from the intracellular stores and by intercellular propagation of the Ca(2+)-wave. The [Ca2+]i-transient upon mechanical stimulation of LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes was limited and/or variable. In CPAE cells only the intracellular release is important for evoking the Ca(2+)-transient, and is followed by IC. IC can occur via gap junctions (GJ) consisting of membrane-spanning proteins, connexins (Cx). It was demonstrated that IC and GJ in RPE and ROS cells can be reversibly blocked by gap-junction inhibitors such as heptanol or halothane. We demonstrated important differences in modulation of gap junctional communication between these cell types. While in RPE cells stimulation of PKC activity was able to inhibit IC, this was not the case in ROS cells. We screened LE-RPE cDNA via PCR using specific primers for different connexins and found no effect of high glucose solutions, which cause decreased intercellular communication, on the Cx-isoforms expressed. Cx43 is the only Cx-isoform present at the protein level for which Western blot analysis revealed the presence of different forms corresponding to different phosphorylated states. Increased phosphorylation of Cx43 was only seen after direct PKC activation by PMA, but not by indirect PKC activation by high glucose levels. The decreased communication by high glucose concentrations was however associated by a decreased expression of cellular Cx43 to about 3/4 of the level in control conditions. High glucose concentrations therefore decrease Cx43 at the protein level via a PKC effect that appears to be independent of the direct activation of PKC by phorbolesters. Mechanical stimulation did not evoke intercellular Ca(2+)-waves in LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes. In CPAE-endothelial cells, the contribution of gap junctions to IC following mechanical stimulation is negligible, and modulation of gap junctions via phosphorylation or high glucose solutions is absent. Perfusion experiments and pharmacological studies demonstrated that IC following mechanical stimulation of these cells occurs via release of an extracellular mediator. Our experiments provide strong evidence in favor of purinergic agonists as mediators, such as ATP but mainly ADP. In conclusion we can say that cells contain a wide spectrum of mechanisms for intra- and intercellular communication, and that widely different mechanisms can evoke the same phenomenon of intra- and intercellular Ca(2+)-waves.

Animals↗