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PubMed2006

Kinetics of endothelin-induced inhibition and glucose permeability of astrocyte gap junctions.

Gap junctions contribute to important functions of communicating glial cells in brain physiology and pathology. Endothelins (ETs), a vasoactive family of peptides present in the brain, have been described as potent inhibitors of astrocyte gap junctional communication. Through dye-coupling studies we demonstrate here that this inhibition occurs rapidly and then successively reverses and returns to control levels after 90 min of continuous ET1 or ET3 exposure. In addition, long-term exposure of cells to ET3, which acts mainly on ETB receptors, also desensitized the acute action of ET1, which was previously shown to act through either ETA or ETB receptor sites, or both. The gap junction blocker carbenoxolone did not show any time-dependent desensitization and was fully effective also in cultures treated with ETs for prolonged times. The ETs inhibitory effects were partially prevented when blocking pertussis toxin-sensitive G-proteins, chelating intracellular Ca2+, or omitting extracellular Ca2+. We further show that ETs modulate gap junction-mediated transfer of 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-Y1)amino]-2-deoxyglucose (2-NBDG), a fluorescent glucose molecule, indicating a role of astrocyte gap junction coupling in metabolic trafficking and suggesting the importance of these peptides in the control of intercellular diffusion of energetic compounds. These findings might have particular relevance in early tissue reactions after various cerebral injuries, which commonly involve increased cerebral ET levels.

4-Chloro-7-nitrobenzofurazan↗
PubMed1984

Phorbol ester tumor promoter affects the mouse epidermal gap junctions.

Gap junctions are known to mediate cell to cell coupling. This study shows that the potent tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), drastically affects the presence of gap junctions between mouse interfollicular epidermal (IFE) cells. In a time course ultrastructural study after a single application of 1 microgram of TPA the gap junctions between the IFE basal cells begin to decrease by 10 h post-exposure, are totally absent between 18 h and 30 h, and start reappearing at 30 h after TPA application. The potent hyperplasiogen , but very weak tumor promoter, mezerein, produces comparable hyperplasia and wide intercellular spaces but the population of gap junctions remains unchanged.

Animals↗
PubMed1998

Diverse functions of vertebrate gap junctions.

Gap junctions are clusters of intercellular channels between adjacent cells. The channels are formed by the direct apposition of oligomeric transmembrane proteins, permitting the direct exchange of ions and small molecules (< 1 kDa) between cells without involvement of the extracellular space. Vertebrate gap junction channels are composed of oligomers of connexins, an enlarging family of proteins consisting of perhaps > 20 members. This article reviews recent advances in understanding the structure of intercellular channels and describes the diverse functions attributable to gap junctions as a result of insights gained from targeted gene disruptions in mice and genetic disease in humans.

Animals↗
PubMedDate not supplied

Two homologous protein components of hepatic gap junctions.

Gap junctions consist of closely packed pairs of transmembrane channels, the connexons, through which materials of low relative molecular mass diffuse from the cell to neighbouring cells. In liver, connexons consist of six protein subunits which, until now, were believed to be identical. However, besides the major polypeptide of relative molecular mass (Mr) 28,000 (and see refs 4 and 6), a component of Mr 21,000 (21K) has been repeatedly observed in liver. The amino-terminal sequence (18 residues) of this less abundant protein shows that it is related to, but distinct from, the Mr 28K protein. Immuno-staining and immuno-precipitation show both proteins to be in the same gap junctional plaques. Thus, it seems that hepatic gap junction channels (and by extension possibly others) are composed of two (or more) homologous proteins.

Amino Acid Sequence↗
PubMed1988

Tissue and species conservation of the vertebrate and arthropod forms of the low molecular weight (16-18000) proteins of gap junctions.

Gap junctions have been isolated from four murine tissues, from rat and Xenopus laevis liver, and from Nephrops norvegicus (Norway lobster) hepatopancreas. The preparations of gap junctions from each vertebrate tissue contain a single major protein, Mr 16,000, and those from Nephrops hepatopancreas a protein, Mr 18,000. Immunocytochemical studies using affinity-purified antibodies raised against gap junctions from Nephrops show the junctional origin of the 18k protein. Immunological studies using Western blotting and biochemical studies using tryptic peptide mapping show no significant differences between the 16k junctional proteins of mouse and hence provide no evidence of tissue variation. These studies also suggest that the mouse, rat, and Xenopus 16k proteins and the Nephrops 18k protein share some common structural features.

Animals↗
PubMed1998

The polarized hepatic human/rat hybrid WIF 12-1 and WIF-B cells communicate efficiently in vitro via connexin 32-constituted gap junctions.

Gap junction intercellular communication (GJIC) plays an essential role in the control of growth, differentiation, and functions of different tissues. The expression of connexins (Cxs), the structural proteins of gap junctions, is developmentally regulated and tissue-specific. In vivo hepatocytes express Cx32 and Cx26. Most currently available in vitro hepatic cell systems express Cx43 instead of the expected Cxs. This work analyzes the GJIC competence and Cx expression of the highly differentiated and polarized hepatoma-derived hybrid cell lines, WIF 12-1 and WIF-B. It shows (using two dye transfer assays) that both lines communicate efficiently and that the acquisition of GJIC competence precedes the formation of bile canaliculi. Interestingly, these cells communicate via Cx32 expression, whereas Cx26 and Cx43 are not expressed, as demonstrated by Western and Northern blotting, immunocytochemistry, and confocal microscopy. The human fibroblast W138 parent communicates via Cx43, whereas the rat hepatoma parent Fao and the subclone WIF 12-1 TGdelta, that has lost the human X chromosome, do not communicate, the expression of Cx32 being restricted to the mRNA in these two lines. The GJIC competence of WIF cells could thus result from the activation of the human X chromosome-linked Cx32 gene.

Animals↗
PubMed1993

Identification of a proline residue as a transduction element involved in voltage gating of gap junctions.

Gap junction channels are structurally distinct from other ion channels in that they comprise two hemichannels which interact head-to-head to form an aqueous channel between cells. Intercellular voltage differences together with increased intracellular concentrations of H+ and Ca2+ cause closure of these normally patent channels. The relative sensitivity to voltage varies with the subunit (connexin) composition of the channels. The third of four transmembrane-spanning regions (M3) in connexins has been proposed to form the channel lining, and a global 'tilting' of the hemichannel subunits has been correlated with channel closure. But specific components involved in transduction of channel gating events have not been identified in either gap junctions or other ion channel classes (however, see model in ref. 5). We have examined a strictly conserved proline centrally located in M2 of connexin proteins. Mutation of this proline (Pro 87) in connexin 26 causes a reversal in the voltage-gating response when the mutant hemichannel is paired with wild-type connexin 26 in the Xenopus oocyte system. This suggests that the unique properties associated with this residue are critical to the transduction of voltage gating in these channels.

Amino Acid Sequence↗
PubMed2006

Role of connexin43-interacting proteins at gap junctions.

Gap junctions are arrays of cell-to-cell channels that allow diffusion of small molecules between neighboring cells. The individual channels are formed by the four-transmembrane connexin (Cx) proteins. Recently, multiple proteins have been found to interact at the cytoplasmic site with the most abundant connexin, Cx43, but physiological data about the role of these interactions is scarce. Here, molecular detail about Cx43 interactions is presented and the putative roles of Cx43-interacting proteins are discussed. Emphasis is on new insights into the interactions of c-Src and ZO-1 with Cx43, interacting proteins discovered within the last 2 years (drebrin, CIP85, CCN3), and feedback between gap junctions, adherens junctions (N-cadherin and catenins) and the cytoskeleton (microtubules and actin).

Acidosis↗
PubMed2002

Peptides acting at gap junctions.

Gap junction channels are low resistance pathways allowing an action potential to propagate from one cell to the neighboring. Moreover, small molecules (<1000 Da) may pass the channel providing a possibility for metabolic coupling, growth and differentiation control of a cell by its surrounding. Antiarrhythmic peptides can enhance the conductivity of the channels while other peptides, angiotensin or extracellular loop peptides, reduce intercellular communication. On the other hand, peptides like angiotensin II or endothelin-1 can increase expression of certain gap junction channel proteins and, thereby, may affect intercellular coupling chronically. Thus, intercellular communication can be controlled using peptide drugs.

Amino Acid Motifs↗
PubMed2005

Role of intramolecular interaction in connexin50: mediating the Ca2+-dependent binding of calmodulin to gap junction.

Gap junction channels formed by connexin50 (Cx50) are critical for maintenance of eye lens transparency. Cleavage of the carboxyl terminus (CT) of Cx50 to produce truncated Cx50 (Cx50trunc) occurred naturally during maturation of lens fiber cells. The mechanism of its altered properties is under confirmation. It has been suggested that calmodulin (CaM) participates in gating some kinds of gap junction. Here, we performed confocal colocalization and co-immunoprecipitation experiments to study the relationships between Cx50 and CaM. Results exhibited that the CaM could colocalize Ca2+ dependently with CT in the linear area of cell-to-cell contact formed by Cx50trunc, while it could not localize in the linear area without expression of CT. Further study indicated that the CT could interact Ca2+ independently with the cytoplasmic loop (CL) of Cx50. These data put forward the importance of Ca2+-independent intramolecular interaction between CT and CL of Cx50, which mediate the Ca2+-dependent binding of CaM to Cx50. These intra- and intermolecular interactions may further improve our understanding of biological significance of the Cx50 in the eye lens.

Binding Sites↗
PubMed1984

Isolation and characterisation of arthropod gap junctions.

Gap junctions have been isolated from the hepatopancreas of the crustacean arthropod, Nephrops norvegicus (Norway lobster). SDS-PAGE of these preparations shows two major protein bands, mol. wt. 18 000 (18 K) and mol. wt. 28 000 (28 K). The 18-K and 28-K proteins are interconvertible, cannot be distinguished by two dimensional tryptic and chymotryptic peptide mapping, and therefore appear to be different (most likely monomeric and dimeric) forms of the same protein. The protein can also aggregate to higher multimeric forms mol. wt. 38 000 (presumed trimer), and mol. wt. 52 000 (presumed tetramer). The buoyant density of the isolated gap junctions in continuous potassium iodide gradients is 1.260 g/cm. The junctions are progressively solubilized in increasing SDS concentrations, mostly between 0.1% and 0.2% SDS, and this is accompanied by the release of the 18-K and 28-K forms of the junctional protein. The Nephrops hepatopancreas 18-K junctional protein has antigenic determinants in common with the vertebrate 16-K junctional protein as shown by cross-reactivity with two different affinity purified antibody preparations. However, no detectable similarity can be seen between the major I-labelled tryptic and chymotrytpic peptides of the Nephrops hepatopancreas 18-K protein and the mouse liver 16-K protein.

Journal Article↗
PubMed1988

Organization of connexons in isolated rat liver gap junctions.

Gap junction plaques from rat liver plasma membranes have been subjected to a range of detergent treatments in order to evaluate systematically the influence of different isolation procedures on their structure. The separation of the connexons was found to vary depending on the conditions used. In the absence of detergent the center-to-center separation of the connexons is, on average, approximately 90 A, and they are arranged on a hexagonal lattice so that the symmetry of the double-layered structure approximates to p6m in projection (or p622 in three-dimensions). Exposure to increasing concentration of detergent reduces the connexon separation to values below 80 A. More severe detergent treatment leads to disintegration of the gap junction plaques. Specimens with center-to-center separations smaller than 86 A show progressively larger deviation from p6m symmetry, seen as apparent rotations of the connexon assemblies within the crystal lattice. This reorganization occurs with both ice-embedded and negatively-stained specimens, using ionic or nonionic detergents, and therefore is probably a packing readjustment caused by depletion of intervening lipid molecules.

Animals↗
PubMed2001

Effects of ginsenosides from Panax ginseng on cell-to-cell communication function mediated by gap junctions.

Gap junctions have been shown or are believed to be involved in the pathogenesis of many inherited and acquired human diseases. Agents that regulate the gap junction-mediated intercellular communication (GJIC) function may facilitate prevention and treatment of GJIC-involved diseases. In the present study we examined the effects of 27 ginsenosides isolated from Panax ginseng on GJIC. The results show that compounds 1 (oleanolic acid), 2 (ginsenoside-R0), 3 (ginsenoside-Rb1), 5 (ginsenoside-Rb2), 7 (ginsenoside-Rd), 8 (ginsenoside-Rg3), 12 (panaxadial), 13 (notoginsenoside-R4), 17 [ginsenoside-Rg2 (20S)], 18 (ginsenoside-Rf), and 26 (ginsenoside-F3) did not obviously affect GJIC, whereas compounds 4 (ginsenoside-Rc), 6 (ginsenoside-Rb3), 9 (ginsenoside-Rd2), 10 (notoginsenoside-Fe), 11 (ginsenoside-Rh2),14 (ginsenoside-Ra1), 15 (ginsenoside-Re), 16 [ginsenoside-Rg2 (20R)], 19 (ginsenoside-Ia), 20 [ginsenoside-Rh1 (20S)], 21 [ginsenoside-Rh1 (20R)], 22 (ginsenoside-F1), 23 (protopanaxatriol), 24 (panaxatriol), 25 (ginsenoside-Rg1), and 27 (chikusetsaponin-L8) induced GJIC reductions at various degrees. Compounds 2, 7, and 8 protected against the tyrosine phosphatase inhibitor vanadate-induced GJIC reduction, while compounds 1, 5, 7, and 17 inhibited the cytokine interleukin 1 alpha (IL-1alpha)-induced reduction in GJIC. Nevertheless, no compounds protected against the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced GJIC inhibition. On the other hand, GJIC reductions induced by compounds 6, 9,10, 20, 21, 22, 24, and 25 were inhibited by the tyrosine kinase (TK) inhibitor genistein, while GJIC reductions induced by compounds 6, 9, 14, 16, 19, 21, and 24 were attenuated in the presence of the PKC inhibitor calphostin C. However, GJIC reductions induced by compounds 4, 23, and 27 were not inhibited either by genistein or by calphostin C. These data indicate that various mechanisms are responsible for effects of ginsenosides on GJIC.

Cell Communication↗
PubMed2006

Pharmacology of cardiovascular gap junctions.

Gap junction (GJ) channels play an important role in forming a functional network or syncytium of cells by allowing the transfer of small molecules or the conduction of electrical activation. These channels can be regulated at the level of acute opening or closure as well as at the level of expression including synthesis, protein trafficking and degradation. Many of the underlying mechanisms depend on phosphorylation or dephosphorylation of connexins. A number of drugs is available to study GJ function and connexin expression. Some of these drugs have shown therapeutic effects, e.g. the anti-arrhythmic peptides AAP10 and ZP123 in the prevention of certain types of arrhythmia. Moreover, mediators involved in cardiovascular pathophysiology, e.g. angiotensin, endothelin, tumor necrosis factor-alpha, fibroblast growth factor and others, affect connexin expression and can alter the Cx43/Cx40 ratio, which may contribute to the formation of an arrhythmogenic substrate. On the other hand, drugs affecting these mediators may influence GJ networking and may thus open new therapeutic horizons.

Animals↗
PubMed2005

Heterocellular contact at the myoendothelial junction influences gap junction organization.

Heterocellular communication between vascular smooth muscle cells (VSMC) and endothelial cells (EC) at the myoendothelial junction (MEJ) is a critical part of control of the arteriolar wall. We have developed an in vitro model of the MEJ composed of primary cultures of murine EC and VSMC. Immunoctytochemistry and immunoblots demonstrated Cx37 and Cx43 in both cell types, whereas Cx40 was found only in EC. Cx37 was excluded from the MEJ in both EC and VSMC. Connexin composition as well as functionality of the gap junctions at the MEJ was assessed by measuring diffusional transfer of biocytin and Cy3. Using connexin-specific blockers and manipulations of expression of individual connexin proteins, we confirmed that Cx37 is not a part of EC-VSMC coupling, and we demonstrated that heterotypic gap junctions are functional at the MEJ. We speculate that specific gap junction organization may be a vital component of EC-VSMC contact at the MEJ.

Animals↗
PubMed1989

Cardiac gap junctions and gap junction-associated vesicles: ultrastructural comparison of in situ negative staining with conventional positive staining.

By comparing in situ negative staining of mammalian heart muscle using La(NO3)3 with conventional positive staining by uranium and lead salts, we showed that 1) the membrane area of rat cardiac gap junctions (GJs) at the intercalated disks is threefold to fourfold greater than previously thought; 2) connexon arrays of cardiac GJ are subdivided into microdomains by connexon-free aisles; 3) profiles of GJ-associated vesicles (GJAVs) of plasmalemmal origin (which are present extracellularly and sharply localized at three extracellular sites) are paired to form GJs with each other and with myocyte plasmalemma; 4) some GJAVs contain arrays of assembled connexons; and 5) myocytes contain intracytoplasmic complexes lying within cylindrical or cigar-shaped membranes and consisting of GJs and multiple vesicles apparently dissociating from these GJs.

Animals↗
PubMed1992

Biophysics of gap junctions.

Gap junction channels, now known to be formed of connexins, connect the interiors of apposed cells. These channels can be opened and closed by various physiological stimuli and experimental treatments. They are permeable to ions and neutral molecules up to a size of about 1 kDa or 1.5 nm diameter, including second messengers and metabolites. The processes of gating and of permeation are the subject of this review. Voltage is a readily applied stimulus, and transjunctional voltages, or those between cytoplasm and exterior, affect most junctions. Single channel transitions between open and closed states are rapid and presumably involve a charge movement as occurs with channels of electrically excitable channels of nerve and muscle. Identification of gating domains and charges by domain replacement and site-directed mutagenesis is being pursued. Raising cytoplasmic H+ or Ca2+ concentrations rapidly reduces junctional conductance, and this action is generally reversible, at least in part. A number of lipophilic alcohols, fatty acids and volatile anesthetics have similar actions. Phosphorylation also modulates junctional conductance, and in several cases, sites of phosphorylation are known. These gating processes appear similar to those induced by voltage. Permeability measurement indicates that the channel is aqueous and that permeation is by diffusion with only minor interactions with the channel wall. Differences among junctions are known, but further characterization of connexin and cell specificity is required.

Animals↗
PubMed1992

Acid phosphatase localization in endocytosed horizontal cell gap junctions.

Gap junction (GJ) endocytosis appears to be part of a cycle of GJ renewal in horizontal cells of the teleost fish retina. At least three stages of GJ endocytosis in these neurons have been identified using conventional electron microscopy (EM): invagination of GJ membranes (GJ blebs); free GJ vesicles; and GJ vesicle fusion with mature lysosomes (Vaughan & Lasater, 1990a). In the present study, EM-level acid phosphatase (AP) histochemistry of white bass retina was used to determine at what stage enzymatic degradation of endocytosed GJs begins. Electron-dense AP reaction product was observed within the trans face of the Golgi apparatus, mature lysosomes, and occasional, internal GJ vesicles. In contrast, GJ blebs, peripheral GJ vesicles, and most internal GJ vesicles lacked AP reaction product. These results support the idea that at least some of the GJ vesicles observed within these retinal neurons arise from endocytosis, are on a degradative pathway, and can be termed GJ "endosomes." Furthermore, GJ vesicles appear to be initially free of AP, but some later acquire it (presumably from transport vesicles bearing degradative enzymes). It is still unclear whether our previous report of GJ vesicle fusion with mature lysosomes is a subsequent step in GJ degradation or part of a different degradative pathway altogether.

Acid Phosphatase↗