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PubMed1998

Enhanced secretion of amylase from exocrine pancreas of connexin32-deficient mice.

To determine whether junctional communication between pancreatic acinar cells contributes to their secretory function in vivo, we have compared wild-type mice, which express the gap junctional proteins connexin32 (Cx32) and connexin26, to mice deficient for the Cx32 gene. Pancreatic acinar cells from Cx32 (-/-) mice failed to express Cx32 as evidenced by reverse transcription-PCR and immunolabeling and showed a marked reduction (4.8- and 25-fold, respectively) in the number and size of gap junctions. Dye transfer studies showed that the extent of intercellular communication was inhibited in Cx32 (-/-) acini. However, electrical coupling was detected by dual patch clamp recording in Cx32 (-/-) acinar cell pairs. Although wild-type and Cx32 (-/-) acini were similarly stimulated to release amylase by carbamylcholine, Cx32 (-/-) acini showed a twofold increase of their basal secretion. This effect was caused by an increase in the proportion of secreting acini, as detected with a reverse hemolytic plaque assay. Blood measurements further revealed that Cx32 (-/-) mice had elevated basal levels of circulating amylase. The results, which demonstrate an inverse relationship between the extent of acinar cell coupling and basal amylase secretion in vivo, support the view that the physiological recruitment of secretory acinar cells is regulated by gap junction mediated intercellular communication.

Amylases↗
PubMed1987

Proteoglycans and glycosaminoglycans induce gap junction synthesis and function in primary liver cultures.

Intercellular communication via gap junctions, as measured by dye and electrical coupling, disappears within 12 h in primary rat hepatocytes cultured in serum-supplemented media or within 24 h in cells in a serum-free, hormonally defined medium (HDM) designed for hepatocytes. Glucagon and linoleic acid/BSA were the primary factors in the HDM responsible for the extended life span of the electrical coupling. After 24 h of culture, no hormone or growth factor tested could restore the expression of gap junctions. After 4-5 d of culture, the incidence of coupling was undetectable in a serum-supplemented medium and was only 4-5% in HDM alone. However, treatment with glycosaminoglycans or proteoglycans of 24-h cultures, having no detectable gap junction protein, resulted in synthesis of gap junction protein and of reexpression of electrical and dye coupling within 48 h. Most glycosaminoglycans were inactive (heparan sulfates, chondroitin-6 sulfates) or only weakly active (dermatan sulfates, chondroitin 4-sulfates, hyaluronates), the weakly active group increasing the incidence of coupling to 10-30% with the addition of 50-100 micrograms/ml of the factor. Treatment of the cells with 50-100 micrograms/ml of heparins derived from lung or intestine resulted in cells with intermediate levels of coupling (30-50%). By contrast, 10-20 micrograms/ml of chondroitin sulfate proteoglycan, dermatan sulfate proteoglycan, or liver-derived heparin resulted in dye coupling in 80-100% of the cells, with numerous cells showing dye spread from a single injected cell. Sulfated polysaccharides of glucose (dextran sulfates) or of galactose (carrageenans) were inactive or only weakly active except for lambda-carrageenan, which induced up to 70% coupling (albeit no multiple coupling in the cultures). The abundance of mRNA (Northern blots) encoding gap junction protein and the amounts of the 27-kD gap junction polypeptide (Western blots) correlated with the degree of electrical and dye coupling indicating that the active glycosaminoglycans and proteoglycans are inducing synthesis and expression of gap junctions. Thus, proteoglycans and glycosaminoglycans, especially those found in abundance in the extracellular matrix of liver cells, are important in the regulation of expression of gap junctions and, thereby, in the regulation of intercellular communication in the liver. The relative potencies of heparins from different tissue sources at inducing gap junction expression are suggestive of functional tissue specificity for these glycosaminoglycans.

Animals↗
PubMed1992

Chemopreventive effects of green tea components on hepatic carcinogenesis.

Catechin components of green tea have been shown to possess anticarcinogenic properties possible related to their antioxidant activity. In the present study, a catechin containing green tea extract (GTE) was examined for its effect on three previously defined properties of liver tumor promoters, induction of cytolethality, inhibition of gap junctional intercellular communication, and induction of cell proliferation. Hepatocytes from male B6C3F1 mice were isolated and placed in primary culture. The effects of GTE of oxygen free radical-induced cytolethality was examined by coincubating GTE with the oxygen radical generating compounds paraquat, glucose oxidase (GO), and xanthine oxidase (XO). GTE prevented the induction of hepatocyte cytolethality by GO, XO, and paraquat in a dose-responsive manner. Similarly, GTE prevented the inhibition of gap junctional-mediated intercellular communication (measured by lucifer yellow dye coupling) by phenobarbital, lindane, and paraquat in a dose-dependent manner. The effect of GTE on hepatocyte DNA synthesis was examined in male mice containing preneoplastic liver lesions induced by diethylnitrosamine. GTE significantly decreased the labeling index in hepatic preneoplastic foci from animals treated with phenobarbital for 7 days. These studies suggest that the previous reported anticarcinogenic activity of green tea may be related to its effect on the tumor promotion stage of the cancer process.

Animals↗
PubMed2000

Connexins: a connection with the skin.

The intercellular signaling system mediated by connexin channels is crucial for maintaining tissue homeostasis, growth control, development, and synchronized response of cells to stimuli. This review summarizes the structure, assembly, and properties of the components of the complex and diverse connexin system, and their biological functions in skin. The importance of gap junctional intercellular communication for normal development and differentiation of human epidermis as well as the hearing function of the inner ear is illustrated by the examples of erythrokeratodermia variabilis and palmoplantar keratoderma associated with hearing loss. These autosomal dominant inherited disorders are caused by germline mutations in the connexin genes GJB3 (encoding connexin-31) and GJB2 (encoding connexin-26), respectively. Recent functional studies of individual connexin mutations suggest that they may exert a dominant inhibitory effect on normal connexin channel function and perturb gap junctional intercellular communication, resulting in phenotypic manifestation in patients with these disorders.

Cell Communication↗
PubMed1998

Genetic toxicity of N-methylcarbamate insecticides and their N-nitroso derivatives.

N-Methylcarbamate esters are an important group of insecticides. They have lower acute toxicity to vertebrates than organophosphates, although their genotoxicity has not been adequately studied. Here we investigate the cytotoxicity and genotoxicity of N-methylcarbamate insecticides and their N-nitroso derivatives in Chinese hamster V79 cells, using the hprt locus as a marker, and also assess inhibition of gap junctional intercellular communication. N-Methylcarbamate insecticides were chemically N-nitrosated to obtain the N-nitroso derivatives. N-Nitrosation greatly increased the cytotoxicity and mutagenicity of N-methylcarbamates at the hprt locus in Chinese hamster V79 cells. The mutagenic potential of N-nitroso-N-methylcarbamates was much higher than those of many other known mutagenic nitroso compounds, as well as some non-nitroso mutagenic alkylating agents. Parental N-methylcarbamates themselves were not mutagenic, however, they inhibited gap junctional intercellular communication half as effectively as the well-studied tumor promoter 12-O-tetradecanoylphorbol-13-acetate. The findings show that N-methylcarbamate insecticides and their N-nitroso derivatives have the potential to act through mediation of epigenetic and genotoxic mechanisms respectively in the multiple stages of chemical carcinogenesis.

Aldicarb↗
PubMedDate not supplied

Altered dye diffusion and upregulation of connexin37 in mouse aortic endothelium deficient in connexin40.

Connexin40 (Cx40), connexin37 (Cx37) and connexin43 (Cx43) are subunit proteins of gap junction channels in the vascular wall which are presumably involved in the propagation of vasomotor signals. In this study we have investigated in Cx40-deficient versus wild-type aortic endothelium to which extent loss of Cx40 impairs intercellular communication. We show in Cx40-deficient mice that expression of both Cx37 and Cx43 protein was increased approximately 3- and 2-fold over the level in wild-type endothelium, respectively. Furthermore, Cx37 immunosignals were distributed more homogeneously on contacting plasma membranes in Cx40-deficient versus with wild-type endothelium. Cx43 was not detected in endothelium but only in smooth muscle cells of the vessel wall. Iontophoretic injection of Lucifer Yellow or neurobiotin into aortic endothelium of Cx40-deficient mice showed extensive intercellular transfer of neurobiotin but not of Lucifer Yellow. In contrast, intercellular spreading of Lucifer Yellow was observed in endothelium of wild-type aorta. As shown by electron microscopy, gap junctions in Cx40-deficient endothelium were morphologically different from those of wild-type vessels. These results demonstrate that dye diffusibility of endothelial gap junctions is different in Cx40-deficient and wild-type mice, although Cx40-deficient mice retain the capability of intercellular communication. Apparently, Cx40-deficient endothelial cells upregulate and redistribute Cx37 as a molecular adaptation to the lack of Cx40.

Animals↗
PubMed1985

Evolutionary origins of neuropeptides, hormones, and receptors: possible applications to immunology.

Immune function requires intercellular communication. The vocabulary includes messenger molecules closely linked to the immune system as well as more widely acting messengers such as hormones and neuroactive substances. To try to bring these together, we have used an evolutionary approach. Materials that resemble hormonal peptides and neuropeptides, previously thought to be restricted to multicellular animals, are present in protozoa, bacteria, and higher plants. There is also evidence for substances in microbes that bind hormones and other messengers, which resemble receptors of vertebrates. Therefore, we suggest that the molecules of intercellular communication probably arose much earlier in evolution than the endocrine, nervous, and immune systems. This insight provides new understanding of messenger systems in vertebrates, as applied to the immune system, as well as new insights into possible disease mechanisms, including those that involve autoimmunity.

Allergy and Immunology↗
PubMed2005

Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells.

BACKGROUND: HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed. METHODS: Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL. RESULTS: Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade. CONCLUSION: The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.

Anti-Inflammatory Agents↗
PubMed2002

IL-1beta-induced production of metalloproteinases by synovial cells depends on gap junction conductance.

Synovial cells can form networks connected by gap junctions. The purpose of this study was to obtain evidence for a necessary role of gap junction intercellular communication in protein secretion by synovial cells. We developed a novel assay to measure the enzymatic activity of metalloproteinases (MMPs) produced by synovial cells in response to interleukin-1beta (IL-1beta) and employed the assay to explore the biological function of gap junctions. IL-1beta produced a dose-dependent increase in MMP activity that was blocked by exposure to the gap junction inhibitors 18alpha-glycyrrhetinic acid and octanol for as few as 50 min. The inhibitors produced an immediate and marked reduction in intercellular communication, as assessed by transient current analysis using the nystatin perforated-patch method. These observations suggest that communication through gap junctions early in IL-1beta signal transduction is critical to the process of cytokine-regulated secretion of MMPs by synovial cells.

Animals↗
PubMed2005

Connexin-made channels as pharmacological targets.

Gap junctions are clusters of intercellular channels that provide morphological support for direct diffusion of ions and low-molecular-weight molecules between adjacent coupled cells. Each gap junction channel is made by docking of two hemichannels or connexons, each formed by assembly of six proteins (connexins). 21 members of the connexin gene family are likely to be expressed in the human genome. These ubiquitous gated channels, allowing rapid intercellular communication and synchronisation of coupled cell activities, play critical roles in many signalling processes, including co-ordinated cardiac and smooth muscle contractions, neuronal excitability, neurotransmitter release, insulin secretion, epithelial electrolyte transport, etc. Mutational alterations in the connexin genes are associated with the occurrence of multiple pathologies, such as peripheral neuropathies, cardiovascular diseases, dermatological diseases, hereditary deafness and cataract. But the neuro- and cardioprotective effects of blocking agents of junctional channels show that closure of these channels may also be beneficial in certain pathological situations. Consequently, modulation of gap junctional intercellular communication is a potential pharmacological target. In contrast to most other membrane channels, no natural toxin or specific inhibitor of junctional channels has been identified yet and most uncoupling agents generally also affect other ionic channels and receptors. Future research, based for example on the recent developments in genetics, may clarify gap junction physiology. This will in turn provide promising perspectives for the development of targeted drugs.

Amino Acid Sequence↗
PubMed2005

Evolution of gap junction proteins--the pannexin alternative.

Gap junctions provide one of the most common forms of intercellular communication. They are composed of membrane proteins that form a channel that is permeable to ions and small molecules, connecting the cytoplasm of adjacent cells. Gap junctions serve similar functions in all multicellular animals (Metazoa). Two unrelated protein families are involved in this function; connexins, which are found only in chordates, and pannexins, which are ubiquitous and present in both chordate and invertebrate genomes. The involvement of mammalian pannexins to gap junction formation was recently confirmed. Now it is necessary to consider the role of pannexins as an alternative to connexins in vertebrate intercellular communication.

Amino Acid Sequence↗
PubMed2000

Analysis of gap junction assembly using mutated connexins detected in Charcot-Marie-Tooth X-linked disease.

The assembly of gap junction intercellular communication channels was studied by analysis of the molecular basis of the dysfunction of connexin 32 mutations associated with the X-linked form of Charcot-Marie-Tooth disease in which peripheral nervous transmission is impaired. A cell-free translation system showed that six recombinant connexin 32 mutated proteins-four point mutations at the cytoplasmic amino terminus, one at the membrane aspect of the cytoplasmic carboxyl terminus, and a deletion in the intracellular loop-were inserted into microsomal membranes and oligomerised into connexon hemichannels with varying efficiencies. The functionality of the connexons was determined by the ability of HeLa cells expressing the respective connexin cDNAs to transfer Lucifer yellow. The intracellular trafficking properties of the mutated connexins were determined by immunocytochemistry. The results show a relationship between intracellular interruption of connexin trafficking, the efficiency of intercellular communication, and the severity of the disease phenotype. Intracellular retention was explained either by deficiencies in the ability of connexins to oligomerise or by mutational changes at two targeting motifs. The results point to dominance of two specific targeting motifs: one at the amino terminus and one at the membrane aspect of the cytoplasmically located carboxyl tail. An intracellular loop deletion of six amino acids, associated with a mild phenotype, showed partial oligomerisation and low intercellular dye transfer compared with wild-type connexin 32. The results show that modifications in trafficking and assembly of gap junction channels emerge as a major feature of Charcot-Marie-Tooth X-linked disease.

Animals↗
PubMed2005

Connexin43 with a cytoplasmic loop deletion inhibits the function of several connexins.

Connexins (Cx) form gap junction channels mediating direct intercellular communication. To study the role of amino acids within the cytoplasmic loop, we produced a recombinant adenovirus containing Cx43 with a deletion of amino acids 130-136 (Cx43del(130-136)). Cx43del(130-136) expressed alone in HeLa cells localized within the cytoplasm and did not allow transfer of ions, neurobiotin or Lucifer yellow. When co-expressed with wild type Cx43, Cx43del(130-136) blocked electrical coupling and transfer of neurobiotin or Lucifer yellow. Cx43del(130-136) and Cx43 co-localized by immunofluorescence and were co-purified from Triton X-100-solubilized cell extracts. Intercellular transfer mediated by Cx37 and Cx45 (but not Cx26 or Cx40) was inhibited when co-expressed with Cx43del(130-136). Cx43del(130-136) co-localized with Cx37, Cx40, or Cx45, but not Cx26. These data suggest that Cx43del(130-136) produces connexin-specific inhibition of intercellular communication through formation of heteromeric connexons that are non-functional and/or retained in the cytoplasm.

Amino Acid Substitution↗
PubMed1998

Induction of differentiation of the cultured rat mammary epithelial cells by triterpene acids.

We investigated the effects of triterpene acids (TAs), ursolic acid (UA) and oleanolic acid (OA), on the induction of proliferation and differentiation of normal rat mammary epithelial cells (RMEC) or organoids cultured in Matrigel or primary culture system. To elucidate the effects, we tested their differentiation inducing activities with intercellular communication ability, cell cycle patterns, induction of apoptosis, and morphological differentiation in the three dimensional extracellular culture system. To study the changes of RMEC subpopulation in culture, the cultured cells were isolated, immunostained with peanut lectin (PNA) and anti-Thy-1.1 antibody and then analyzed with flow cytometry. Four different subpopulations, such as PNA and Thy-1.1 negative cells (B-), PNA positive cells (PNA+), Thy-1.1 positive cells (Thy-1.1+), PNA and Thy-1.1 positive cells (B+), were obtained and the size of each subpopulation was changed in culture with time in the presence of TAs. Intercellular communication was observed in culture for 7 days in TAs-treated cells, but not in culture for 4 days with scrape-loading dye transfer technique. G2/M phase cells and the number of apoptotic population were increased in TAs-treated groups in cell cycle analyses. S phase fractions were reduced and the change of G1 phase cells was not observed. The colonies with distinct multicellular structures, such as stellate, ductal, webbed, squamous, lobulo-ductal colonies, were observed in Matrigel culture and the frequencies of each colony were changed in the presence of TAs. These results suggest that UA and OA have differentiation inducing effects on rat mammary epithelial cells in primary or in Matrigel culture.

Animals↗
PubMed2002

c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes.

Loss of gap junctions and impaired intercellular communication are characteristic features of pathological remodeling in heart failure as a result of stress or injury, yet the underlying regulatory mechanism has not been identified. Here, we report that in cultured myocytes, rapid loss of the gap junction protein connexin43 (Cx43) occurs in conjunction with the activation of c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, on stress stimulation. To investigate the specific role of JNK activation in the regulation of connexin in cardiomyocytes, an activated mutant of mitogen-activated protein kinase kinase 7 (mutant D), a JNK-specific upstream activator, was expressed in myocytes by adenovirus-mediated gene transfer. JNK activation in infected cardiomyocytes resulted in significant reduction of Cx43 expression at both mRNA and protein levels and impaired cell-cell communication. To evaluate the role of JNK in the regulation of Cx43 expression and gap junction structure in vivo, a Cre-LoxP-mediated gene-switch system was used to establish a transgenic animal model with targeted activation of JNK in ventricular myocardium. The transgenic hearts exhibited significant downregulation of Cx43 expression and loss of gap junctions in myocardium that may contribute to the cardiac dysfunction and premature death phenotype. Our report represents the first evidence, both in vitro and in vivo, implicating JNK as an important mediator of stress-induced Cx43 downregulation and impaired intercellular communication in the failing heart.

Animals↗
PubMed1991

In-vitro testing and the carcinogenic potential of several nitrosated indole compounds.

4-chloro-methoxyindole is a naturally occurring compound in Vicia faba which can easily react with nitrite to form a N-nitroso compound. In this in vitro study, the potential genotoxic effects of nitrosated 4-chloro-6-methoxyindole and its structural analogue 4-chloroindole were evaluated for the first time by using both Salmonella and Chinese hamster V79 cells. Additionally, the inhibition of gap junctional intercellular communication in V79 cells by these compounds was determined; this is a validated parameter for tumor-promoting activity. Most assays were also performed with nitrosated indole-3-acetonitrile, a naturally occurring compound in brassicas. Both nitrosated chloroindoles were highly mutagenic to Salmonella typhimurium TA100 without the need of exogenous metabolic activation and were potent inducers of Sister Chromatid Exchanges. Nitrosated indole-3-acetonitrile generated the same effects, although at much higher concentrations. Equivocal results were obtained for the nitrosated chloroindoles in a forward mutation assay using the hypoxanthine guaninephosphoribosyltransferase locus. All nitrosated indole compounds significantly inhibited gap junctional intercellular communication. These results indicate that nitrosated chloroindoles and nitrosated indole-3-acetonitrile should be considered as mutagens and agents with potential tumor-promoting capacity.

Animals↗
PubMed1986

Evidence for physiological regulation of myometrial gap junction permeability.

We have investigated whether direct intercellular communication between uterine smooth muscle cells of delivering rats is influenced by intracellular adenosine 3',5'-cyclic monophosphate concentration ([cAMPi]) and agents relevant to the hormonal control of pregnancy and parturition. The rate of diffusion of phosphorylated 2-[3H]deoxy-D-glucose (2-DG) in strips of longitudinal myometrium from rats in labor, indicated by the apparent diffusion coefficient for this molecule, was observed to be significantly reduced in tissues with elevated [cAMPi] (after treatment with dibutyryl cAMP, 8-bromo cAMP, forskolin, and theophylline) in the absence of any change in the area of gap junctions (GJs). Similarly, several agonists that elevate [cAMPi] in this tissue (e.g., isoproterenol, relaxin, carbacyclin, prostaglandin E2) also reduced 2-DG diffusion. These data suggest that the permeability of GJs in uterine smooth muscle may be regulated by [cAMPi] and physiologically relevant agonists. Control of GJ permeability may be important for the physiological regulation of intercellular communication and the extent of synchronous contractile activity in the uterine wall during pregnancy and parturition.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2005

Molecular and cellular insights into the coxsackie-adenovirus receptor: role in cellular interactions in the stem cell niche.

In recent years, progress has been made in characterizing the molecular and cellular elements that are responsible for the regeneration in the damaged brain and highlighting the key role of the stromal-vascular 'environment' to orchestrate secondary neurogenesis and repair. Indeed, the ability of the stem cells to self-renew and differentiate is tightly regulated by stromal ependymal cells and endothelial cells expressing molecular cues that constitute the extracellular stem cell 'niche'. Several soluble growth factors such as EGF, TGFbeta, FGF2, SDF-1alpha and Noggin are important signals for the stem cell niche but little is known about the role of membrane-bound molecules in intercellular communications between the niche and the stem cells. In this mini-review, we highlight the emerging role of a family of adhesion molecules in the control of secondary neurogenesis. The coxsackie-adenovirus receptor (CAR) is a 46 kDa transmembrane protein and a member of the immunoglobulin super family. It is close structurally and evolutionary to other adhesion molecules involved in cell-cell interactions during embryogenesis, broadly expressed in the developing central nervous system but restricted to ependymal cells in the adult brain. This unique location and its newly established signalling properties further support the role of CAR in intercellular communications. Elucidating the other signalling molecules and manipulating the stromal-vascular niche for example by adenovirus gene therapy remain important goals for future clinical applications.

Animals↗