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At least 19 recordsLinked to original sources
PubMed1993

Tight-junction tightness of Necturus gall bladder epithelium is not regulated by cAMP or intracellular Ca2+. II. Impedance measurements.

In the preceding publication we have reported that, contrary to the prevailing opinion in the literature, the tight-junction tightness of Necturus gall bladder epithelium is not up-regulated by cAMP-mediated or by Ca(2+)-mediated stimulation. This conclusion was based on our observation that the stimulant-induced increase in transepithelial resistance (Rt) occurred only when the lateral intercellular spaces were allowed to collapse, which suggested that the increase reflected primarily or exclusively the increasing resistance of the lateral spaces (Rlis) rather than the postulated increase in tight-junction resistance (Rj). An alternative explanation could have been that the constancy of Rt after space dilatation reflected an increase Rj that was masked by a concomitant fall in apical and basolateral cell membrane resistances Ra and Rbl. To decide between those possibilities we have performed impedance measurements with transepithelial and intracellular microelectrodes on Necturus gall bladder epithelium. Applying previously developed analysis procedures, the measurements readily showed that elevation of intracellular Ca2+ concentration increased Rlis, but left Rj as well as Ra and Rbl quasi constant. Experiments with forskolin, theophylline or isobutylxanthine, on the other hand, were less clear. These stimulants activated an apical Cl- conductance, which drastically reduced Ra and apparently caused low-frequency polarization effects that could not be accounted for by the classical epithelial equivalent circuit. After elimination of the polarization phenomena by uni- or bilateral substitution of Cl- by isethionate or sulphate, however, we were able to demonstrate that Rj remains constant under cAMP-mediated stimulation irrespective of whether the lateral spaces are kept open or are allowed to collapse. We conclude that the tight-junction resistance of Necturus gall bladder epithelium is not controlled by intracellular Ca2+ or by cAMP-mediated stimulation.

Animals↗
PubMed1993

Tight-junction tightness of Necturus gall bladder epithelium is not regulated by cAMP or intracellular Ca2+. I. Microscopic and general electrophysiological observations.

Following the publications by Duffey et al. [Nature 294:451 (1981)] and Palant et al. [Am J Physiol 245: C203 (1983)] it is generally accepted that tight-junction tightness of Necturus gall bladder epithelium is up-regulated by cAMP-mediated and Ca(2+)-mediated stimulation. This conclusion was mainly based on observed increases in transepithelial resistance (Rt). However, since in leaky epithelia Rt cannot be simply equated with the tight junction resistance (Rj), but may include large contributions from the lateral space resistance (Rlis), we asked whether the observed increases in Rt resulted indeed from Rj or whether Rlis also increased. The experiments were performed on Necturus gall bladders using forskolin or the Ca2+ ionophore A23187 as stimulants. Forskolin (2 mumol/l) had a biphasic effect. In the first 5 min Rt decreased from 128 +/- 13 to 119 +/- 14 omega cm2 (P < 0.05, n = 10) which probably reflects stimulation of an apical cell membrane Cl- conductance (see accompanying paper). Subsequently Rt increased in approximately 30 min to 184 +/- 20 omega cm2 and then remained fairly constant. Simultaneously the lateral spaces collapsed. If the spaces were now transiently opened by passing mucosa-positive direct current across the epithelium, Rt fell transiently to 111 +/- 7 omega cm2, but returned gradually to its elevated level when the spaces collapsed again. When the spaces were constantly dilated by a serosa-positive hydrostatic pressure of 1 cm H2O, forskolin neither affected the space width nor increased Rt, and current passage was virtually ineffective, although the cells depolarized in response to forskolin as usual.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Pentalaminar specialized membrane junctions - tight junctions - are described in the granular layer of the pigeon cerebellum. The presence of these axo-dendritique and dendrosomatic contacts suggest the existence of electrotonic coupling in the pigeon cerebellum.

Pentalaminar specialized membrane junctions - tight junctions - are described in the granular layer of the pigeon cerebellum. The presence of these axo-dendritique and dendrosomatic contacts suggest the existence of electrotonic coupling in the pigeon cerebellum.

Animals↗
PubMed2000

Molecular physiology and pathophysiology of tight junctions III. Tight junction regulation by intracellular messengers: differences in response within and between epithelia.

Tight junction permeability differs with the type of permeants, their size, and their charge. Selective changes in permeability do occur, and they illustrate the diversity in functional reactions of tight junctions. This suggests that special structures in the tight junctions are involved. More and more structural components of the tight junctions are becoming known. The divergence in behavior of native tissue and filter-grown epithelial monolayers with respect to the effects of intracellular messengers offers the possibility to relate structure and function. In addition to the tools for conventional permeability studies, probes have become available to detect changes in activation of intracellular effector proteins such as the protein kinase C isotypes, and with in situ imaging techniques the way is open for a functional approach in the study of tight junctions.

Animals↗
PubMed2000

Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins.

Tight junctions form the major paracellular barrier in epithelial tissues. Barrier-sealing properties are quite variable among cell types in terms of electrical resistance, solute and water flux, and charge selectivity. A molecular explanation for this variability appears closer following identification of the transmembrane proteins occludin and members of the claudin multigene family. For example, the human phenotype of mutations in claudin-16 suggests that it creates a channel that allows magnesium to diffuse through renal tight junctions. Similarly, a mouse knockout of claudin-11 reveals its role in formation of tight junctions in myelin and between Sertoli cells in testis. The study of other claudins is expected to elucidate their contributions to creating junction structure and physiology in all epithelial tissues.

Animals↗
PubMed1999

VAP-33 localizes to both an intracellular vesicle population and with occludin at the tight junction.

Tight junctions create a regulated intercellular seal between epithelial and endothelial cells and also establish polarity between plasma membrane domains within the cell. Tight junctions have also been implicated in many other cellular functions, including cell signaling and growth regulation, but they have yet to be directly implicated in vesicle movement. Occludin is a transmembrane protein located at tight junctions and is known to interact with other tight junction proteins, including ZO-1. To investigate occludin's role in other cellular functions we performed a yeast two-hybrid screen using the cytoplasmic C terminus of occludin and a human liver cDNA library. From this screen we identified VAP-33 which was initially cloned from Aplysia by its ability to interact with VAMP/synaptobrevin and thus was implicated in vesicle docking/fusion. Extraction characteristics indicated that VAP-33 was an integral membrane protein. Antibodies to the human VAP-33 co-localized with occludin at the tight junction in many tissues and tissue culture cell lines. Subcellular fractionation of liver demonstrated that 83% of VAP-33 co-isolated with occludin and DPPIV in a plasma membrane fraction and 14% fractionated in a vesicular pool. Thus, both immunofluorescence and fractionation data suggest that VAP-33 is present in two distinct pools in the cells. In further support of this conclusion, a GFP-VAP-33 chimera also distributed to two sites within MDCK cells and interestingly shifted occludin's localization basally. Since VAP-33 has previously been implicated in vesicle docking/fusion, our results suggest that tight junctions may participate in vesicle targeting at the plasma membrane or alternatively VAP-33 may regulate the localization of occludin.

Animals↗
PubMed1993

The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions.

Tight junctions form an intercellular barrier between epithelial cells, serve to separate tissue compartments, and maintain cellular polarity. Paracellular sealing properties vary among cell types and are regulated by undefined mechanisms. Sequence of the full-length cDNA for human ZO-1, the first identified tight junction component, predicts a protein of 1736 aa. The N-terminal 793 aa are homologous to the product of the lethal(1)discs-large-1 (dlg) tumor suppressor gene of Drosophila, located in septate junctions, and to a 95-kDa protein located in the postsynaptic densities of rat brain, PSD-95. All three proteins contain both a src homology region 3 (SH3 domain), previously identified in membrane proteins involved in signal transduction, and a region homologous to guanylate kinase. ZO-1 contains an additional 943-aa C-terminal domain that is proline-rich (14.1%) and contains an alternatively spliced domain, whose expression was previously shown to correlate with variable properties of tight junctions. dlg mutations result in loss of apical-basolateral epithelial cell polarity and in neoplastic growth. These results suggest a protein family specialized for signal transduction on the cytoplasmic surface of intercellular junctions. These results also provide biochemical evidence for similarity between invertebrate septate and vertebrate tight junctions. The C-terminal domain of ZO-1, and its alternatively spliced region, appears to confer variable properties unique to tight junctions.

Alternative Splicing↗
PubMed2005

Paracellin-1 and the modulation of ion selectivity of tight junctions.

Tight junctions play a key selectivity role in the paracellular conductance of ions. Paracellin-1 is a member of the tight junction claudin protein family and mutations in the paracellin-1 gene cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe renal Mg2+ wasting. The mechanism of paracellin-1 function and its role in FHHNC are not known. Here, we report that in LLC-PK1 epithelial cells paracellin-1 modulated the ion selectivity of the tight junction by selectively and significantly increasing the permeability of Na+ (with no effects on Cl-) and generated a high permeability ratio of Na+ to Cl-. Mutagenesis studies identified a locus of amino acids in paracellin-1 critical for this function. Mg2+ flux across cell monolayers showed a far less-pronounced change (compared to monovalent alkali cations) following exogenous protein expression, suggesting that paracellin-1 did not form Mg2+-selective paracellular channels. We hypothesize that in the thick ascending limb of the nephron, paracellin-1 dysfunction, with a concomitant loss of cation selectivity, could contribute to the dissipation of the lumen-positive potential that is the driving force for the reabsorption of Mg2+.

Amino Acid Sequence↗
PubMed2000

Transmembrane proteins of tight junctions.

Tight junctions from a morphological and functional boundary between the apical and basolateral cell surface domains of epithelia and endothelia, and regulate selective diffusion along the paracellular space. Two types of four-span transmembrane proteins, occludin and claudins, as well as the single-span protein JAM are associated with tight junctions. The functional analysis of these proteins starts to reveal how they are involved in the functions of tight junctions, which of their domains are important for these functions, and how they interact with each other to form the junctional diffusion barriers.

Animals↗
PubMedDate not supplied

Maintenance of the epithelial barrier in a bronchial epithelial cell line is dependent on functional E-cadherin local to the tight junctions.

Tight junctions (TJ) are essential components of polarized epithelia, and E-cadherin is important for their formation and maintenance. The bronchial epithelial cell line, 16HBE14o-expresses E- and P-cadherin, but not N-cadherin. E- and P-cadherin levels changed during culture, the former increasing after confluence, and the latter were markedly reduced. All detectable E-cadherin was bound to beta- and gamma-catenins. We investigated involvement of E-cadherin with epithelial integrity using an E-cadherin specific, function-blocking antibody, SHE78-7. Surprisingly, apical SHE78-7 exposure caused a prompt fall in transepithelial resistance (TER), while TER remained unchanged for 8 hrs after basal exposure then dropped. SHE78-7 exposure increased epithelial permeability to mannitol, inulin, and 9.5 kDa and 77 kDa dextrans and caused fragmentation and loss of the tight junction protein, ZO-1, from the cell borders in some areas. Ultrastructural studies showed that all junctional intercellular contact was lost in the center of SHE78-7 induced lesions. Near the lesion periphery, epithelial structure was maintained, but TJs were dysfunctional as shown by ruthenium red penetration. Analysis of epithelial penetration by SHE78-7 revealed discrete, local defects in the apical barrier at the top of some cell hills that permitted rapid access of the antibody to E-cadherin near the apical surface. In contrast, after basal exposure, antibody initially engaged with E-cadherin nearer the basal surface and only accessed apical E-cadherin later. Taken together with the TER measurements, these data suggest compartmentalization of E-cadherin function within 16HBE14o-cells, with only the apical E-cadherin adjacent to the tight junctions contributing to the function of the latter.

Animals↗
PubMed1998

Tight junctions.

Tight junctions are the most apical intercellular junctions of epithelial and endothelial cells and create a regulatable semipermeable diffusion barrier between individual cells. On a cellular level, they form an intramembrane diffusion fence that restricts the intermixing of apical and basolateral membrane components. In addition to these well defined functions, more recent evidence suggests that tight junctions are also involved in basic cellular processes like the regulation of cell growth and differentiation.

Animals↗
PubMed2001

Multifunctional strands in tight junctions.

Tight junctions are one mode of cell-cell adhesion in epithelial and endothelial cellular sheets. They act as a primary barrier to the diffusion of solutes through the intercellular space, create a boundary between the apical and the basolateral plasma membrane domains, and recruit various cytoskeletal as well as signalling molecules at their cytoplasmic surface. New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell-cell adhesion apparatus in molecular terms.

Animals↗
PubMed1999

Structural and signalling molecules come together at tight junctions.

Tight junctions (TJs) have been suggested to act both as barriers and fences, but lack of information on the constituents of TJ strands has hampered the direct assessment of these functions. Over the past year, our understanding of the molecular architecture of TJ strands has increased markedly and we are ready to experimentally examine how TJs are involved in their dual functions.

Animals↗
PubMed2003

Signalling to and from tight junctions.

Tight junctions have long been regarded as simple barriers that separate compartments of different compositions, but recent research indicates that different types of signalling proteins and transduction pathways are associated with these junctions. They receive and convert signals from the cell interior to regulate junction assembly and function, and transmit signals to the cell interior to modulate gene expression and cell behaviour.

Animals↗
PubMed2000

The structure and function of claudins, cell adhesion molecules at tight junctions.

Tight junctions (TJs) play a pivotal role in compartmentalization in multicellular organisms by sealing the paracellular pathway in epithelial and endothelial cell sheets. Recently, novel integral membrane proteins, claudins, have been identified as major cell adhesion molecules working at TJs. Claudins comprise a multigene family, and each member of approximately 23 kDa bears four transmembrane domains. To date, 15 members of this gene family have been identified. When expression vectors of each species of claudins were transfected into fibroblasts lacking endogenous claudins or TJs, well-developed TJs were observed between adjacent transfectants. Furthermore, claudins were shown to be directly involved in the barrier function of TJs by experiments using Clostridium perfringens enterotoxin. Now that claudins have been identified, the structure and functions of TJs should be determined in detail in molecular terms.

Animals↗
PubMed1993

The structure and regulation of tight junctions.

Tight junctions create a paracellular barrier between both epithelial and endothelial cells. Recent advances have helped define their molecular composition and regulation. Studies in cultured cell lines provide new insights into how assembly and barrier properties may be controlled by signal transduction cascades.

Animals↗
PubMed1998

Rho GTPase signaling regulates tight junction assembly and protects tight junctions during ATP depletion.

Tight junctions control paracellular permeability and cell polarity. Rho GTPase regulates tight junction assembly, and ATP depletion of Madin-Darby canine kidney (MDCK) cells (an in vitro model of renal ischemia) disrupts tight junctions. The relationship between Rho GTPase signaling and ATP depletion was examined. Rho inhibition resulted in decreased localization of zonula occludens-1 (ZO-1) and occludin at cell junctions; conversely, constitutive Rho signaling caused an accumulation of ZO-1 and occludin at cell junctions. Inhibiting Rho before ATP depletion resulted in more extensive loss of junctional components between transfected cells than control junctions, whereas cells expressing activated Rho better maintained junctions during ATP depletion than control cells. ATP depletion and Rho signaling altered phosphorylation signaling mechanisms. ZO-1 and occludin exhibited rapid decreases in phosphoamino acid content following ATP depletion, which was restored on recovery. Expression of Rho mutant proteins in MDCK cells also altered levels of occludin serine/threonine phosphorylation, indicating that occludin is a target for Rho signaling. We conclude that Rho GTPase signaling induces posttranslational effects on tight junction components. Our data also demonstrate that activating Rho signaling protects tight junctions from damage during ATP depletion.

Adenosine Triphosphate↗
PubMed2005

Tight junctions, from tight intercellular seals to sophisticated protein complexes involved in drug delivery, pathogens interaction and cell proliferation.

Tight junctions (TJ) are intercellular seals that regulate the passage of ions and molecules through the paracellular pathway. This property allows epithelial and endothelial sheets to function as barriers between different body compartments. Although TJ were identified by electron microscopy since the 1950's, the analysis in recent years of their molecular composition, has depicted TJ as signaling complexes involved in a wide spectrum of physiological and pathological processes, such as cell growth and differentiation, cancer and metastasis, and pathogen interaction. This new knowledge has in turn given rise to novel strategies for enhancing the paracellular flux of poorly absorbed therapeutics.

Animals↗