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PubMed2005

Decreased cellular membrane expression of gap junctional protein, connexin 43, in rat detrusor muscle with chronic partial bladder outlet obstruction.

OBJECTIVES: To investigate alterations in gap junctional protein, connexin-43 (Cx-43), in the rat detrusor muscle with partial bladder outlet obstruction (P-BOO). Muscle cell actions, such as detrusor contractions, are thought to be synchronized by way of gap junctional intercellular communication. Gap junctions may play an important role in voiding, and P-BOO is a common medical problem. METHODS: A total of 33 female Wistar rats (12 weeks old) were divided into a P-BOO group and a sham-operated control group and were killed at 2, 4, and 8 weeks after surgery. Cystometric investigation, the alteration of gap junction, and Cx-43 protein expression, which compose the gap junction, were examined. RESULTS: The number of gap junctions was decreased in the P-BOO rat bladder. Furthermore, decreased cellular membrane expression of Cx-43 proteins was detected in rat detrusor muscle cells more than 4 weeks after surgery. The gap junctions of the detrusor muscle cell membranes were significantly fewer in number in the P-BOO rats with no detrusor contractions. CONCLUSIONS: These data suggest that the normal signals that contribute to voiding function could be transported directly through the gap junctions. Voiding dysfunction may be caused by the disruption of gap junctional intercellular communication.

Animals↗
PubMed1991

Desmosomal glycoprotein DGI, a component of intercellular desmosome junctions, is related to the cadherin family of cell adhesion molecules.

Among the variety of specialized intercellular junctions, those of the adherens type have the most obvious association with cytoskeletal elements. This may be with the actin microfilament system as in the zonula adherens or with intermediate filaments as in the macula adherens, or desmosome. In the former case, it is clear that transmembrane glycoproteins of the cadherin family are important adhesive components of the molecular assembly. We now show for desmosomes that a major glycoprotein component (desmosomal glycoprotein DGI) has extensive homology with the cadherins, defining an extended family, but also has unique features in its cytoplasmic domain that are likely to be relevant to the association with intermediate rather than actin filaments. A novel 282-residue extension contains repeats of approximately 29 amino acid residues predicted to have an antiparallel beta-sheet structure, followed by a glycine-rich sequence. As in the cadherins, the extracellular domain contains possible Ca2(+)-binding sequences and a potential protease processing site. The cell adhesion recognition region (His-Ala-Val) of the cadherins is modified to Arg-Ala-Leu.

Amino Acid Sequence↗
PubMed2002

Gap junction-mediated intercellular communication in ischemic preconditioning.

Gap junction-mediated communication can modulate cell death in different tissues. In myocardium, gap junction communication is altered during ischemia, which contributes to the development of arrhythmias, but still allows synchronization of the onset of rigor contracture in the progression of injury. During reperfusion, gap junction communication allows cell-to-cell spread of hypercontracture and cell death. Since the intracellular signal transduction systems involved in modulation of gap junction-mediated communication are activated during ischemic preconditioning, the hypothesis can be raised that gap junctions are end-effectors of preconditioning contributing to its protective effect on cell death. This paper reviews the available information supporting this hypothesis. It has been shown that ischemic preconditioning may influence gap junction-mediated intercellular communication by activation of different kinases, including PKC and MAPK cascades, and by preservation of cGMP among other mechanisms. Connexin phosphorylation by PKC, p38/MAPK, and PKG, tends to reduce intercellular communication. This effect of ischemic preconditioning seems to have no relevant consequences during prolonged ischemia, and does not significantly modify the time course of either electrical uncoupling or the frequency or temporal distribution of ventricular arrhythmias during this period. However, any modification of gap junction communication during initial reperfusion could contribute to the reduced extent of hypercontracture and cell death observed in preconditioned hearts. The potential role of gap junctions as effectors of ischemic preconditioning against lethal injury secondary to ischemia-reperfusion deserves to be investigated in depth.

Animals↗
PubMed1997

Propagation of mechanically induced intercellular calcium waves via gap junctions and ATP receptors in rat liver epithelial cells.

Mechanical stimulation was used to initiate Ca2+ waves in rat liver epithelial cells in order to ascertain the degree to which gap junctional intercellular communication (GJIC) is involved in communication of Ca2+ to adjacent cells and to assess alternative Ca2+ signaling pathways that may be present between these cells. In both WB-F344 cells, which show a high degree of GJIC, and WB-aB1 cells, which are GJIC deficient, mechanical stimulation of a single cell induced a Ca2+ wave which propagated away from the point of stimulation, across cell borders, to neighboring cells directly or indirectly in contact with the stimulated cell. In addition, the Ca2+ wave was transmitted to nearby isolated cells that exhibited no direct or indirect contact with the stimulated cell. Treatment of cells with 18beta-glycyrrhetinic acid, a compound that has been shown to block GJIC, did not significantly affect propagation of the Ca2+ wave. In contrast, treatment with suramin, a P2-purinergic receptor inhibitor, significantly reduced both the rate and the extent of Ca2+ wave propagation in WB-F344 cells and completely blocked its propagation in WB-aB1 cells. Cotreatment with suramin and glycyrrhetinic acid was found to completely block the mechanically induced Ca2+ wave in both cell lines. These studies indicate that mechanically induced cell injury in rat liver epithelial cells initiates signaling through at least two pathways, involving intercellular communication via gap junctions and extracellular communication via ATP activation of purinergic receptors.

Animals↗
PubMed1998

Normal differentiation of cultured lens cells after inhibition of gap junction-mediated intercellular communication.

The cells of the vertebrate lens are linked to each other by gap junctions, clusters of intercellular channels that mediate the direct transfer of low-molecular-weight substances between the cytosols of adjoining cells. Although gap junctions are detectable in the unspecialized epithelial cells that comprise the anterior face of the organ, both their number and size are greatly increased in the secondary fiber cells that differentiate from them at the lens equator. In other organs, gap junctions have been shown to play an important role in tissue development and differentiation. It has been proposed, although not experimentally tested, that this may be true in the lens as well. To investigate the function of gap junctions in the development of the lens, we have examined the effect of the gap junction blocker 18beta-glycyrrhetinic acid (betaGA) on the differentiation of primary cultures (both dissociated cell-derived monolayers and central epithelium explants) of embryonic chick lens epithelial cells. We found that betaGA greatly reduced gap junction-mediated intercellular transfer of Lucifer yellow and biocytin throughout the 8-day culture period. betaGA did not, however, affect the differentiation of these cells into MP28-expressing secondary fibers. Furthermore, inhibition of gap junctions had no apparent effect on either of the two other types of intercellular (adherens and tight) junctions present in the lens. We conclude that the high level of gap junctional intercellular communication characteristic of the lens equator in vivo is not required for secondary fiber formation as assayed in culture. Up-regulation of gap junctions is therefore likely to be a consequence rather than a cause of lens fiber differentiation and may primarily play a role in lens physiology.

Administration, Topical↗
PubMed1986

Epithelial cell adhesion molecules.

Recognition and binding between cells are of fundamental importance for a proper function of multicellular organisms, both during embryonic development and in the adult stage. Recently several cell surface proteins that are involved in these phenomena have been discovered. In the identification of these proteins, called cell adhesion molecules (CAMs), immunological methods have played a significant role. In a different approach to studies of cell-cell binding at the molecular level, the chemical composition of intercellular junctions is being studied. Intercellular junctions are specialized cell surface domains that have been identified by electron microscopy. They are particularly well developed in epithelia. Several proteins in the junctions have now been identified and characterized. This review deals with the biochemical properties of epithelial CAMs, and those proteins that are candidates for cell-to-cell binding in the junctions. In particular, the relationships between the various CAMs and junctional proteins are discussed. The tentative biological functions of these molecules are also considered.

Animals↗
PubMed2001

Chronic effects of endothelin 1 and angiotensin II on gap junctions and intercellular communication in cardiac cells.

Endothelin-1 (ET-1) and angiotensin-II (AT-II) participate in the pathophysiology of cardiovascular diseases. Regulation of gap junctional intercellular communication may influence heart function and its response to cardiac injury. In this study, we examined the effects of ET-1 and AT-II on connexin43 (Cx43) and connexin40 (Cx40) in cultured neonatal rat ventricular cardiomyocytes (NRCs) and the role of mitogen-activated protein kinase signaling in the ET-1- and AT-II-induced responses. NRCs were incubated for 24 h with either ET-1 or AT-II (each at concentrations ranging from 10 to 1000 nM), and Cx43 expression and phosphorylation increased with increasing concentrations of both. ET-1 effects were significantly blocked by ETA (BQ123), but not by ETB (BQ788), receptor antagonists. AT-II-induced Cx43 induction could be completely inhibited by the AT1 receptor antagonist losartan. In contrast to Cx43, Cx40 expression did not change in either ET-1- or in AT-II-treated NRCs. Thus, these two connexins were differentially regulated. ET-1 and AT-II increased the gap junctional conductance between the cardiomyocytes in culture as measured using a dual-cell voltage clamp. Mitogen-activated protein kinase inhibition revealed that ERK1/2 was critical for up-regulation of Cx43 in response to ET-1, whereas both ERK and p38 signal pathways were involved in the regulation of Cx43 by AT-II. Thus, stimulation of the ERK and p38 signal pathways via ETA and AT1 receptors may partcipate in the regulation of cardiac gap junctions under (patho)physiological conditions.

Angiotensin II↗
PubMed1994

Modulation of gap junction-mediated intercellular communication in embryonic chick mesenchyme during tissue remodeling in vitro.

Gap junction-mediated intercellular communication was analyzed in a model system in which tissue necrosis and remodeling could be modulated. This in vitro system, previously used for analysis of epithelial-mesenchymal tissue interaction, was modified to permit analysis of the presence and extent of intercellular communication by monitoring intercellular transfer of the microinjected fluorescent dye, Lucifer Yellow. Light and transmission electronmicroscopy were employed to correlate the presence and degree of gap junctional communication (coupling) with tissue morphology. Digital image analysis was used to determine cell density and mitotic indices within the outgrowths of explants. Our results indicated that cell communication in outgrowths adjacent to necrotic foci within an explant was minimal or absent. Cell-coupling in outgrowths adjacent to a compartment of viable mesenchyme was significantly higher - equivalent to unseparated control cultures. A time-course study demonstrated correlation of increased levels of cell-coupling in outgrowths with the level of tissue remodeling within an explant. Our conclusions from these studies are that embryonic mesenchymal cell populations may be selectively uncoupled as a result of alterations in the microenvironment produced by a proximate impaired cell population. It is proposed that endogenous factors in the microenvironment ("wound signals"), emanating from impaired cell populations, regulate gap junction-mediated intercellular communication in adjacent viable tissue. Normal, unimpaired populations of cells surrounding an area of injury are thereby isolated from the effects of a potentially toxic environment. This could serve as a protective function in development and may represent, in a more general sense, part of the repertoire of events associated with tissue repair and remodeling.

Animals↗
PubMed2003

Modulation of gap junction mediated intercellular communication in TM3 Leydig cells.

Long-term modulation of intercellular communication via gap junctions was investigated in TM3 Leydig cells, under low and high confluence states, and upon treatment of the cells for different times with activators of protein kinase A (PKA) and protein kinase C (PKC). Cells in low confluence were readily coupled, as determined by transfer of the dye Lucifer Yellow; on reaching confluence, the cells uncoupled. Western blots and RT-PCR revealed that connexin 43 (Cx43) was abundantly expressed in TM3 Leydig cells and its expression was decreased after the cells achieved confluence. Stimulation of PKA or PKC induced a decrease in cell-cell communication. Staurosporin, an inhibitor of protein kinases, increased coupling and was able to prevent and reverse the uncoupling actions of dibutyryl cAMP and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Under modulation by confluence, Cx43 was localized to the appositional membranes when cells were coupled and was mainly in the cytoplasm when they were uncoupled. In addition, cAMP and TPA reduced the surface membrane labeling for Cx43, whereas staurosporin increased it. These data show a strong correlation between functional coupling and the membrane distribution of Cx43, implying that this connexin has an important role in intercellular communication between TM3 cells. Furthermore, increased testosterone secretion in response to luteinizing hormone was accompanied by a decrease in intercellular communication, suggesting that gap junction mediated coupling may be a modulator of hormone secretion in TM3 cells.

Animals↗
PubMed2002

Increasing paracellular porosity by E-cadherin peptides: discovery of bulge and groove regions in the EC1-domain of E-cadherin.

PURPOSE: The objective of this work is to evaluate the ability of peptides derived from the bulge (HAV-peptides) and groove (ADT-peptides) regions of E-cadherin EC1-domain to increase the paracellular porosity of the intercellular junctions of Madin-Darby canine kidney (MDCK) cell monolayers. METHODS: Peptides were synthesized using a solid-phase method and were purified using semi-preparative HPLC. MDCK monolayers were used to evaluate the ability of cadherin peptides to modulate cadherin-cadherin interactions in the intercellular junctions. The increase in intercellular junction porosity was determined by the change in transepithelial electrical resistance (TEER) values and the paracellular transport of 14C-mannitol. RESULTS: HAV- and ADT-peptides can lower the TEER value of MDCK cell monolayers and enhance the paracellular permeation of 14C-mannitol. HAV- and ADT-decapeptides can modulate the intercellular junctions when they are added from the basolateral side but not from the apical side; on the other hand. HAV- and ADT-hexapeptides increase the paracellular porosity of the monolayers when added from either side. Conjugation of HAV- and ADT-peptides using omega-aminocaproic acid can only work to modulate the paracellular porosity when ADT-peptide is at the N-terminus and HAV-peptide is at the C-terminus; because of its size, the conjugate can only modulate the intercellular junction when added from the basolateral side. CONCLUSIONS: Peptides from the bulge and groove regions of the EC1 domain of E-cadherin can inhibit cadherin-cadherin interactions, resulting in the opening of the paracellular junctions. These peptides may be used to improve paracellular permeation of peptides and proteins. Furthermore, this work suggests that both groove and bulge regions of EC-domain are important for cadherin-cadherin interactions.

Animals↗
PubMed2002

Bone morphogenetic protein-2 modulation of chondrogenic differentiation in vitro involves gap junction-mediated intercellular communication.

Undifferentiated mesenchymal cells in the limb bud integrate a complex array of local and systemic signals during the process of cell condensation and chondrogenic differentiation. To address the relationship between bone morphogenetic protein (BMP) signaling and gap junction-mediated intercellular communication, we examined the effects of BMP-2 and a gap junction blocker 18 alpha glycyrrhetinic acid (18alpha-GCA) on mesenchymal cell condensation and chondrogenic differentiation in an in vitro chondrogenic model. We find that connexin43 protein expression significantly correlates with early mesenchymal cellular condensation and chondrogenesis in high-density limb bud cell culture. The level of connexin43 mRNA is maximally upregulated 48 h after treatment with recombinant human BMP-2 with corresponding changes in protein expression. Inhibition of gap junction-mediated intercellular communication with 2.5 microM 18alpha-GCA decreases chondrogenic differentiation by 50% at 96 h without effects on housekeeping genes. Exposure to 18alpha-GCA for only the first 24-48 h after plating does not affect condensation or later chondrogenic differentiation suggesting that gap junction-mediated intercellular communication is not critical for the initial phase of condensation but is important for the onset of differentiation. 18alpha-GCA can also block the chondrogenic effects of BMP-2 without effects on cell number or connexin43 expression. These observations demonstrate 18alpha-GCA-sensitive regulation of intercellular communication in limb mesenchymal cells undergoing chondrogenic differentiation and suggest that BMP-2 induced chondrogenic differentiation may be mediated in part through the modulation of connexin43 expression and gap junction-mediated intercellular communication.

Animals↗
PubMedDate not supplied

[Ca ions in regulation of the permeability and mechanical properties of intercellular contacts of small intestinal epithelium].

The role of Ca in regulating passive permeability of alkaline cations is investigated. As it has been shown, the pathway of permeability are intercellular junctions [9-10]. An attempt was made to use permeability parameters for characterizing intercellular junctions. Forms of Ca binding and the nature of site, that discriminated ion permeation are evaluated. To develop the studies of functional peculiarities of intercellular junctions, the role of Ca in regulating the mechanical properties of intercellular junction of small intestine epithelia are investigated.

Animals↗
PubMed1999

Desmosomes: intercellular adhesive junctions specialized for attachment of intermediate filaments.

Cell-cell adhesion is thought to play important roles in development, in tissue morphogenesis, and in the regulation of cell migration and proliferation. Desmosomes are adhesive intercellular junctions that anchor the intermediate filament network to the plasma membrane. By functioning both as an adhesive complex and as a cell-surface attachment site for intermediate filaments, desmosomes integrate the intermediate filament cytoskeleton between cells and play an important role in maintaining tissue integrity. Recent observations indicate that tissue integrity is severely compromised in autoimmune and genetic diseases in which the function of desmosomal molecules is impaired. In addition, the structure and function of many of the desmosomal molecules have been determined, and a number of the molecular interactions between desmosomal proteins have now been elucidated. Finally, the molecular constituents of desmosomes and other adhesive complexes are now known to function not only in cell adhesion, but also in the transduction of intracellular signals that regulate cell behavior.

Animals↗
PubMed2005

[Effect of Shuangshen Tongguan Recipe on nuclear factor-kappa B signal pathway and myocardial junction-mediated intercellular communication in acute myocardial ischemia/reperfusion injured model rats].

OBJECTIVE: To investigate the effects of Shuangshen Tongguan Recipe (SSTG) on myocardial nuclear factor-kappa B (NF-kappaB) signal pathway, expression of myocardial junction intercellular communication (MJIC) connexin 43 (Cx43), and infarcted myocardial size and weight of the rats' heart after acute myocardial ischemia/reperfusion (I/R) damage. METHODS: Model rat of I/R injury was established by coronary arterial ligating/ releasing. The infarcted myocardial size and weight were determined by N-BT staining, expression of NF-kappaB p65 in myocardial tissue and Cx43 were determined by immunohistochemical method, contents of serum tumor necrosis factor-alpha(TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) were measured by ABC-ELISA. RESULTS: The myocardial infarcted size and weight, expression of NF-kappaB p65, contents of serum TNF-alpha and ICAM-1 of I/R injured rats in the model group were significantly increased (P<0.05), while Cx43 degraded markedly after modeling. These changes were restored after treated with SSTG (P <0.05). CONCLUSION: Serious myocardial infarction occurs after ischemia/reperfusion injury, combined with NF-kappaB signal pathway activation and severe Cx43 degradation. SSTG could inhibit the activation of NF-kappaB, the over-excretion of TNF-alpha and ICAM-1 in serum, and the degradation of Cx43 to decrease the myocardial infarcted size and weight.

Animals↗
PubMed1993

Inhibition of intercellular gap junctional communication by alkyl ethers and its modulation by cAMP.

The inhibition of intercellular gap junctional communication (IGJC) by alkyl ethers (ethylene glycol, monomethyl ether, polyethylene glycol 1,000 and polyethylene glycol 6000) was examined using V79 Chinese hamster cells in vitro. Ethylene glycol and monomethyl ether inhibited IGJC very strongly, whilst the other agents inhibited IGJC only insignificantly. When the cells were treated with the combination of two agents, ethylene glycol and monomethyl ether, a significant increase in the inhibition of IGJC occurred. This was probably the result of potentiation rather than an addition effect. The effect of ethylene glycol was antagonized by dibutyryl cyclic adenosine monophosphate (DbcAMP). This effect was most intensive when the cells were treated with both agents at the same time and, in other experimental combinations, the effect was lower but also significant. Caffeine did not influence IGJC either in combination with DbcAMP or by itself.

Animals↗
PubMed1993

Epithelial cells retain junctions during mitosis.

It has long been known that cells show reduced cell-substratum adhesion during mitosis in tissue culture, but it is not generally known whether cell-cell adhesion is also reduced. Epithelial cells, both in culture and in tissues, are linked together by several different types of intercellular junctions. Are these junctions disassembled when epithelial cells divide? Cultured epithelial cells were fluorescently stained for desmosomes, tight junctions and zonulae adherentes, and large numbers of dividing cells examined by light microscopy. The results suggested that all three types of intercellular junctions were retained throughout cell division and no evidence for internalization of junctions was obtained. The persistence of intercellular junctions by cultured cells during division was confirmed by electron microscopy. In order to determine whether intercellular junctions were similarly retained by dividing cells in tissues, human colonic mucosal crypt cells and basal keratinocytes were studied by electron microscopy. Both cell types retained intercellular junctions during division. Dividing basal keratinocytes also possessed hemidesmosomal contact with the basement membrane. It is suggested that retention of cellular junctions during division is important for maintenance of tissue integrity and organization.

Actins↗
PubMed1997

Altered gap junctional communication, intercellular signaling, and growth in cultured astrocytes deficient in connexin43.

Astrocytes are characterized by extensive intercellular communication mediated primarily by gap junction channels composed of connexin43. To examine this junctional protein in astrocytic functions, astrocytes were cultured from embryonic mice with a null mutation in the connexin43 gene (Reaume et al.: Science 267:1831-1834, 1995). Using anti-Cx43 antibodies, immunoblotting and immunostaining indicated that homozygous null astrocytes were devoid of Cx43. They are also deficient in intercellular dye transfer. Astrocytes cultured from heterozygous embryos express significantly lower Cx43 compared to wild type, and their dye coupling is reduced. Markers of glial differentiation, such as glial fibrillary acidic protein and S100, appeared similar in all genotypes. Measurement of intercellular calcium concentration following mechanical stimulation of confluent astrocytes revealed that the number of cells affected by a rise in intracellular calcium was reduced in homozygous cultures compared to wild type. In fact, the calcium response in homozygous astrocytes was similar to that observed in wild-type astrocytes in the presence of a gap junction blocker. The growth rate of astrocytes lacking Cx43 was reduced compared to wild-type astrocytes. These results suggest that gap junctional intercellular communication mediated by Cx43 is not critical for astrocyte differentiation but is likely involved in the regulation of intercellular calcium signaling and cell growth.

Animals↗
PubMed1997

Metabolic trafficking through astrocytic gap junctions.

Astrocytes are interposed between the pericapillary space and neuronal membranes. Consequently, they may represent an important intermediary element between the source of energetic substrates and the main site of energy-consuming elements, respectively, the blood circulation and the neurons. A typical feature of astrocytes is the connections they establish between each other by specialized membrane structures, defined as gap junctions. These intercellular junctions allow direct cell-to-cell exchanges of ions and small molecules, including several compounds involved in major metabolic pathways occurring in astrocytes. The permeability of astrocytes gap junction channels is controlled by several endogenous compounds released by astrocytes themselves or by other brain cell types, including neurons and endothelial cells. In primary cultures of astrocytes, the intercellular diffusion, the utilization and the uptake of glucose and derivates are modified when gap junctional permeability is inhibited by uncoupling agents. Altogether these observations indicate that intercellular pathways constituted by groups of coupled astrocytes could participate to the metabolism and the distribution of energetic substrates throughout the brain.

Animals↗