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PubMedDate not supplied

Synergistic effects of neurons and astrocytes on the differentiation of brain capillary endothelial cells in culture.

Brain capillary endothelial cells form a functional barrier between blood and brain, based on the existence of tight junctions that limit paracellular permeability. Occludin is one of the major transmembrane proteins of tight junctions and its peripheral localization gives indication of tight junction formation. We previously reported that RBE4.B cells (brain capillary endothelial cells), cultured on collagen IV, synthesize occludin and correctly localize it at the cell periphery only when cocultured with neurons. In the present study, we describe a three-cell type-culture system that allowed us to analyze the combined effects of neurons and astrocytes on differentiation of brain capillary endothelial cells in culture. In particular, we found that, in the presence of astrocytes, the neuron-induced synthesis and localization of occludin is precocious as compared to cells cocultured with neurons only.

Animals↗
PubMed2005

Androgens regulate the permeability of the blood-testis barrier.

Within the mammalian testis, specialized tight junctions between somatic Sertoli cells create basal and apical polarity within the cells, restrict movement of molecules between cells, and separate the seminiferous epithelium into basal and adluminal compartments. These tight junctions form the basis of the blood-testis barrier, a structure whose function and dynamic regulation is poorly understood. In this study, we used microarray gene expression profiling to identify genes with altered transcript levels in a mouse model for conditional androgen insensitivity. We show that testosterone, acting through its receptor expressed in Sertoli cells, regulates the expression of claudin 3, which encodes a transient component of newly formed tight junctions. Sertoli cell-specific ablation of androgen receptor results in increased permeability of the blood-testis barrier to biotin, suggesting claudin 3 regulates the movement of small molecules across the Sertoli cell tight junctions. These results suggest that androgen action in Sertoli cells regulates germ cell differentiation, in part by controlling the microenvironment of the seminiferous epithelium. Our studies also indicate that hormonal strategies for male contraception may interfere with the blood-testis barrier.

Androgens↗
PubMed1999

Dodecylphosphocholine-mediated enhancement of paracellular permeability and cytotoxicity in Caco-2 cell monolayers.

The intestinal epithelium is a significant barrier for oral absorption of hydrophilic drugs because they cannot easily traverse the lipid bilayer of the cell membrane and their passage through the intercellular space (paracellular transport) is restricted by the tight junctions. In this report we show that dodecylphosphocholine (DPC) can improve the paracellular permeability of hydrophilic compounds across Caco-2 cell monolayers by modulating the tight junctions. The results show that the alkyl chain as well as the zwitterionic head group of DPC are required for its activity. DPC appears to act by modulating the permeability of tight junctions as evidenced by the fact that treatment of Caco-2 cell monolayers by this agent results in a decreased transepithelial electrical resistance (TEER), increased permeability of paracellular markers (e. g., mannitol) with no change in the permeability of the transcellular marker testosterone, and redistribution of the tight junction-associated protein ZO-1. The effect of DPC on Caco-2 cells (e.g., decrease in TEER) is reversible, and is not caused by gross cytotoxicity (as indicated by the MTT test) or by nonspecific disruption of the cell membrane (as indicated by only slight nuclear staining due to the nonpermeable DNA-specific dye propidium iodide). We propose in the present study a parameter, potency index, that allows comparison of various enhancers of paracellular transport in relation to their cytotoxicity. The potency index is a ratio between the IC(50) value (concentration at which 50% inhibition of control mitochondrial dehydrogenase activity occurs in the MTT test) and the EC(50) value (concentration at which TEER drops to 50% of its control (untreated) value). By this parameter, DPC is significantly safer than the commonly used absorption enhancer palmitoyl carnitine (PC), which has the potency index of approximately 1 (i.e., no separation between effective and toxic concentration).

Caco-2 Cells↗
PubMed2006

Requirements for proximal tubule epithelial cell detachment in response to ischemia: role of oxidative stress.

Sublethal renal ischemia induces tubular epithelium damage and kidney dysfunction. Using NRK-52E rat proximal tubular epithelial cells, we have established an in vitro model, which includes oxygen and nutrients deprivation, to study the proximal epithelial cell response to ischemia. By means of this system, we demonstrate that confluent NRK-52E cells lose monolayer integrity and detach from collagen IV due to: (i) actin cytoskeleton reorganization; (ii) Rac1 and RhoA activity alterations; (iii) Adherens junctions (AJ) and Tight junctions (TJ) disruption, involving redistribution but not degradation of E-cadherin, beta-catenin and ZO-1; (iv) focal adhesion complexes (FAC) disassembly, entangled by mislocalization of paxillin and FAK dephosphorylation. Reactive oxygen species (ROS) are generated during the deprivation phase and rapidly balanced at recovery involving MnSOD induction, among others. The use of antioxidants (NAC) prevented FAC disassembly by blocking paxillin redistribution and FAK dephosphorylation, without abrogating AJ or TJ disruption. In spite of this, NAC did not show any protective effect on cell detachment. H(2)O(2), as a pro-oxidant treatment, supported the contribution of ROS in tubular epithelial cell-matrix but not cell-cell adhesion alterations. In conclusion, ROS-mediated FAC disassembly was not sufficient for the proximal epithelial cell shedding in response to sublethal ischemia, which also requires intercellular adhesion disruption.

Actins↗
PubMed2004

Association of paracellin-1 with ZO-1 augments the reabsorption of divalent cations in renal epithelial cells.

Paracellin-1 (PCLN-1) belongs to the claudin family of tight junction proteins and possibly plays a critical role in the reabsorption of magnesium and calcium. So far, the physiological properties of PCLN-1 have not been clarified. In the present study, we investigated whether PCLN-1 is associated with ZO-1. We also investigated whether (45)Ca(2+) transport across the paracellular barrier is affected by this association. In vitro binding analysis using glutathione S-transferase fusion protein showed that the C-terminal TRV sequence, especially Thr and Val residues, of PCLN-1 interacts with ZO-1. Next, PCLN-1 was stably expressed in Madin-Darby canine kidney cells using a FLAG tagging vector. ZO-1 was co-immunoprecipitated with the wild-type PCLN-1 and the alanine substitution (TAV) mutant. However, mutants of the deletion (Delta TRV) and the alanine substitution (ARV and TRA) inhibited the association of PCLN-1 with ZO-1. Confocal immunofluorescence demonstrated that the wild-type PCLN-1 and the TAV mutant localized in the tight junction along with ZO-1, but the Delta TRV, ARV, and TRA mutants were widely distributed in the lateral membrane including the tight junction area. Interestingly, monolayers of cells expressing the wild-type PCLN-1 and the TAV mutant showed higher activities of (45)Ca(2+) transport from apical to basal compartments, compared with those expressing the Delta TRV, ARV, and TRA mutants and the mock cells. (45)Ca(2+) transport was inhibited by increased magnesium concentration suggesting that magnesium and calcium were competitively transported by PCLN-1. It was noted that a positive electrical potential gradient enhanced (45)Ca(2+) transport from apical to basal compartments without affecting the opposite direction of transport. Thus, PCLN-1 localizes to the tight junction followed by association with ZO-1, and the PCLN-1.ZO-1 complex may play an essential role in the reabsorption of divalent cations in renal epithelial cells.

Absorption↗
PubMed1997

Measurement of paracellular epithelial conductivity by conductance scanning.

A new method, conductance scanning, allows determination of local para- and transcellular conductivities in flat epithelia. Experiments were performed on kidney distal tubule cells, MDCK clone C11, which form monolayers on permeable supports. Above the apical surface, local voltage drops generated by a sinusoidal current clamp were recorded by means of a scanning microelectrode. Data were collected above cell centres and tight junctions. The scanning signal was always significantly higher above the tight junctions, but was uniformly distributed along the junctions. For determination of conductivities two procedures were applied. Method 1: the supraepithelial potential distribution was computed for given trans- and paracellular currents at all positions of the electrode. In a fit algorithm, the currents were varied until the calculated potential difference equalled the voltage measured. Method 2: after collecting scanning data in control Ringer's, intercellular space width was reduced by mucosal addition of 40 mM sucrose and a second set of data was obtained at decreased paracellular, but presumably unchanged transcellular, conductivity. From these data, trans- and paracellular conductivities were calculated. Results of both methods were in excellent agreement. Confluent MDCK-C11 monolayers exhibited a transepithelial conductivity of 13 mS/cm2. The transcellular pathway contributed 2.6 mS/cm2 (20%) and the paracellular pathway 10. 5 mS/cm2 (80%) to the total conductivity. Collapse of the lateral intercellular spaces decreased the paracellular conductivity to 4 mS/cm2 (60%). Confluent MDCK-C11 monolayers constitute true "leaky" epithelia with homogeneously distributed trans- and paracellular conductivities. In conclusion, conductance scanning fills a methodical gap, which hitherto impeded the functional characterization of tight junctions.

Animals↗
PubMed2003

Endocytosis of epithelial apical junctional proteins by a clathrin-mediated pathway into a unique storage compartment.

The adherens junction (AJ) and tight junction (TJ) are key regulators of epithelial polarity and barrier function. Loss of epithelial phenotype is accompanied by endocytosis of AJs and TJs via unknown mechanisms. Using a model of calcium depletion, we defined the pathway of internalization of AJ and TJ proteins (E-cadherin, p120 and beta-catenins, occludin, JAM-1, claudins 1 and 4, and ZO-1) in T84 epithelial cells. Proteinase protection assay and immunocytochemistry revealed orchestrated internalization of AJs and TJs into a subapical cytoplasmic compartment. Disruption of caveolae/lipid rafts did not prevent endocytosis, nor did caveolin-1 colocalize with internalized junctional proteins. Furthermore, AJ and TJ proteins did not colocalize with the macropinocytosis marker dextran. Inhibitors of clathrin-mediated endocytosis blocked internalization of AJs and TJs, and junctional proteins colocalized with clathrin and alpha-adaptin. AJ and TJ proteins were observed to enter early endosomes followed by movement to organelles that stained with syntaxin-4 but not with markers of late and recycling endosomes, lysosomes, or Golgi. These results indicate that endocytosis of junctional proteins is a clathrin-mediated process leading into a unique storage compartment. Such mechanisms may mediate the disruption of intercellular contacts during normal tissue remodeling and in pathology.

Adaptor Protein Complex alpha Subunits↗
PubMed1990

Transforming growth factor beta 1 modulates extracellular matrix organization and cell-cell junctional complex formation during in vitro angiogenesis.

Transforming growth factor-beta 1 (TGF-beta 1) is angiogenic in vivo. In two-dimensional (2-D) culture systems microvascular endothelial cell proliferation is inhibited up to 80% by TGF-beta 1; however, in three-dimensional (3-D) collagen gels TGF-beta 1 is found to have no effect on proliferation while eliciting the formation of calcium and magnesium dependent tube-like structures mimicking angiogenesis. DNA analyses performed on 3-D cell cultures reveal no significant difference in the amount of DNA or cell number in control versus TGF-beta 1 treated cultures. In 2-D cultures TGF-beta 1 is known to increase cellular fibronectin accumulation; however, in 3-D cultures no difference is seen between control and TGF-beta 1 treated cells as established by ELISA testing for type IV collagen, fibronectin, and laminin. In 3-D cultures there is increased synthesis and secretion of type V collagen in both control and TGF-beta 1 treated cultures over 2-D cultures. Even though an equal amount of type V collagen is seen in both 3-D conditions, there is a reorganization of the protein with concentration along an organizing basal lamina in TGF-beta 1 treated cultures. EM morphological analyses on 3-D cultures illustrate quiescent, control cells lacking cell contacts. In contrast, TGF-beta 1 treated cells show increased pseudopod formation, cell-cell contact, and organized basal lamina-like material closely apposed to the "abluminal" plasma membranes. TGF-beta 1 treated cells also appear to form junctional complexes between adjoining cells. Immunofluorescence using specific antibodies to the tight junction protein ZO-1 results in staining at apparent cell-cell junctions in the 3-D cultures. Northern blots of freshly isolated microvascular endothelium, 2-D and 3-D cultures, using cDNA and cRNA probes specific for the ZO-1 tight junction protein, reveal the presence of the 7.8 kb mRNA. Western blots of rat epididymal fat pad endothelial cells (RFC) monolayer lysates probed with anti-ZO-1 label a 220 kd band which co-migrates with the bonafide ZO-1 protein. These data confirm and support the hypothesis that TGF-beta 1 is angiogenic in vitro, eliciting microvascular endothelial cells to form tube-like structures with apparent tight junctions and abluminal basal lamina deposition in three-dimensional cultures.

Animals↗
PubMed1995

Altered hepatic localization and expression of occludin after common bile duct ligation.

Epithelial tight junctions form a regulated barrier that seals the paracellular space and prevents mixing of luminal contents with the interstitium. This barrier is composed of a group of proteins including the putative "sealing" protein occludin that appears to bind directly to a cytoplasmic junction protein, ZO-1. To study the interaction and regulation of these two components when paracellular integrity is altered, we assessed protein expression and immunofluorescent (IF) localization of ZO-1 and occludin in a rat model of hepatocyte tight junction damage induced by common bile duct ligation (CBDL). Protein levels were detected in liver by immunoblotting and IF localization by 3-dimensional reconstruction of serial 0.5-micron confocal microscopic optical sections. As previously described, ZO-1 protein levels progressively increased to threefold control levels 9 days after CBDL. In contrast, occludin protein levels decreased by 50% within 2 days after CBDL and returned to control values by 9 days. In control IF sections, ZO-1 and occludin colocalized, forming thin continuous staining outlining canaliculi. After CBDL, ZO-1 staining appeared discontinuous, and a punctate pericanalicular accumulation of signal developed around junctional areas. Occludin staining was also discontinuous after CBDL, but, in contrast to ZO-1, was not punctate and remained localized either in a linear fashion along canalicular margins or in a homogeneous fashion in immediately surrounding areas. CBDL results in changes in the expression and localization of the putative tight junction sealing protein occludin in hepatocytes that are distinct from those observed for the peripheral membrane tight junction protein ZO-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Test of a two-pathway model for small-solute exchange across the capillary wall.

We previously proposed a two-pathway model for solute and water transport across vascular endothelium (Fu, B. M., R. Tsay, F. E. Curry, and S. Weinbaum. J. Biomech. Eng. 116: 502-513, 1994) that hypothesized the existence of a continuous slit 2 nm wide along tight junction strands within the interendothelial cleft in parallel with 20 x 150-nm breaks in tight junctions. We tested this model by measuring capillary permeability coefficients (P) to a small solute (sodium fluorescein, radius 0.45 nm), assumed to permeate primarily the 2-nm small pore, and an intermediate-sized solute (FITC-alpha-lactalbumin, radius 2.01 nm) excluded from the small pore. Mean values of the paired diffusive permeability coefficients, Psodium fluorescein and PFITC-alpha-lactalbumin, were 34.4 and 2.9 x 10(-6) cm/s, respectively, after corrections for solvent drag and free dye (n = 26). These permeabilities were accounted for by transport through the large-break pathway without the additional capacity of the hypothetical 2-nm pathway. As a further test we examined the relative reductions of Psodium fluorescein and PFITC-alpha-lactalbumin produced by elevated intracellular cAMP. Within 20 min after the introduction of rolipram and forskolin, Psodium fluorescein and PFITC-alpha-lactalbumin decreased to 0.67 and 0.64 times their respective baseline values. These similar responses to permeability decrease were evidence that the two solutes were carried by a common pathway. Combined results in both control and reduced permeability states did not support the hypothesis that a separate pathway across tight junctions is available for solutes with a radius as large as 0.75 nm. If such a pathway is present, then its size must be smaller than that of sodium fluorescein.

Animals↗
PubMed2005

Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo.

Disruption of the intestinal epithelial barrier occurs in many intestinal diseases, but neither the mechanisms nor the contribution of barrier dysfunction to disease pathogenesis have been defined. We utilized a murine model of T cell-mediated acute diarrhea to investigate the role of the epithelial barrier in diarrheal disease. We show that epithelial barrier dysfunction is required for the development of diarrhea. This diarrhea is characterized by reversal of net water flux, from absorption to secretion; increased leak of serum protein into the intestinal lumen; and altered tight junction structure. Phosphorylation of epithelial myosin II regulatory light chain (MLC), which has been correlated with tight junction regulation in vitro, increased abruptly after T cell activation and coincided with the development of diarrhea. Genetic knockout of long myosin light chain kinase (MLCK) or treatment of wild-type mice with a highly specific peptide MLCK inhibitor prevented epithelial MLC phosphorylation, tight junction disruption, protein leak, and diarrhea following T cell activation. These data show that epithelial MLCK is essential for intestinal barrier dysfunction and that this barrier dysfunction is critical to pathogenesis of diarrheal disease. The data also indicate that inhibition of epithelial MLCK may be an effective non-immunosuppressive therapy for treatment of immune-mediated intestinal disease.

Animals↗
PubMed1999

Differential behavior of E-cadherin and occludin in their colocalization with ZO-1 during the establishment of epithelial cell polarity.

At the initial stage of cell-cell contact of epithelial cells, primordial spot-like junctions are formed at the tips of thin cellular protrusions radiating from adjacent cells, where E-cadherin and ZO-1 are precisely coconcentrated (Yonemura et al., 1995, J. Cell Sci. 108:127-142). In fully polarized epithelial cells, E-cadherin and ZO-1 are completely sorted into belt-like adherens junctions (AJ) and tight junctions (TJ), respectively. Here we examined the behavior of occludin, an integral membrane protein consisting of TJ, during the establishment of epithelial cell polarity. Using confocal immunofluorescence microscopy, we quantitatively compared the spatial relationship of occludin/ZO-1 with that of E-cadherin/ZO-1 during epithelial cellular polarization by replating or wounding cultured mouse epithelial cells (MTD1-A). At the initial stage of cell-cell contact, E-cadherin and ZO-1 appeared to be simultaneously recruited to the primordial form of spot-like junctions at the tips of cellular processes which showed no concentration of occludin. Then, as cellular polarization proceeded, occludin was gradually accumulated at the ZO-1-positive spot-like junctions to form belt-like TJ, and in a complementary manner E-cadherin was sorted out from the ZO-1-positive spot-like junctions to form belt-like AJ. The molecular mechanism of TJ/AJ formation during epithelial cellular polarization is discussed with special reference to the roles of ZO-1.

Animals↗
PubMed2005

Effect of lactobacillus on the gut microflora and barrier function of the rats with abdominal infection.

AIM: To investigate the effect of probiotics supplemented by gut on the tight junctions of epithelial cells, barrier function and the microflora of rats with abdominal infection. METHODS: After the model of cecal ligation and perforation established, SD rats were divided into two groups: parenteral nutrition (PN) group and PN+probiotics (probiotics) group, PN solution was supplemented by neck vein and probiotics was delivered via the jejunostomy tube for five days. Vena cava blood and the homogenated tissue of liver, lung and mesenteric lymph nodes were cultured to determine the bacterial translocation rate (BTR). The ultra-structure of epithelial tight junctions and microvilli of the gut were observed by electron microscopy; occluding expression was measured by indirect-immune fluorescence method; anaerobic bacterial growth by anaerobic culture and DNA fingerprint of bacterial colonies of the feces by PCR. RESULTS: The quantity of lactobacteria and bifydobacteria in probiotics group was higher than that of PN group. The profiles of DNA fingerprint expression in probiotics group were similar to that in the normal group, a new 16S rDNA sequence appeared in the profile in PN group. The occludin expression, the integrality of the gut epithelial tight junction and microvilli in probiotics group were improved as compared with PN group. The BTR and endotoxin in blood were reduced more significantly in probiotics group as compared with PN group. CONCLUSION: The probiotics could improve the gut microflora disturbance, increase occludin expression, maintain the gut epithelial tight junction and decrease the bacterial translocations rate.

Animals↗
PubMed2003

Blood-tissue barriers in the male reproductive tract of the dog: a morphological study using lanthanum nitrate as an electron-opaque tracer.

Blood-tissue barriers preventing an uncontrolled exchange of larger molecules between adjacent but metabolically separate compartments have been demonstrated in various organs. One prominent example is the blood-testis barrier which has been investigated in a number of species. A key function of this barrier is to shield developing germ cells from the immune system in order to avoid autoimmune reactions. This requirement also applies to the male excurrent duct system. Yet, very few investigations have addressed the morphology of the blood-epididymal barrier. The goal of the present study, therefore, was to revisit the blood-testis barrier in the dog and to identify the structures constituting the blood-epididymal barrier in this species. Lanthanum nitrate was used as a tracer for electron microscopy. In the testis, lanthanum had free access to the intercellular space of the seminiferous epithelium up to the Sertoli cell junctions. Similarly, epithelial tight junctions were found to represent the permeability barrier in the epididymis. The present study highlights species differences with respect to the blood-testis barrier and extends the knowledge of the blood-epididymal barrier by providing morphofunctional data in this domestic species.

Animals↗
PubMed2006

OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.

Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.

Animals↗
PubMed2003

Serum-derived factors weaken the barrier properties of cultured porcine brain capillary endothelial cells in vitro.

Cultured cerebral capillary endothelial cells are often used as a functional in vitro model of the blood-brain barrier (BBB) to determine drug uptake or to study barrier properties. Usually serum is supplemented to these cultures for cell proliferation. Here, we demonstrate the effect of serum and the serum-derived factors lysophosphatidic acid (LPA) and vascular endothelial growth factor (VEGF) on the barrier properties of cultured porcine brain capillary endothelial cells (PBCEC). Serum prevents tight junction formation of confluent PBCEC monolayers and moreover, opens already established tight junctions shown by decreasing transendothelial electrical resistances (TER). These effects are highly polarised with serum almost exclusively acting from the basolateral side of the cell culture. Immunocytochemistry of PBCEC revealed a delocalisation of the cell border lining tight junction proteins ZO-1, occludin and claudin-5 when serum was added. A serum fraction of 67 kDa was isolated by size-exclusion chromatography, identified as albumin and found to cause a serum-like decrease of the TER. However, fatty acid-free serum albumin does not develop this barrier weakening effect, indicating that small protein-bound factors might be responsible. For instance, serum-bound LPA demonstrated a TER-decreasing effect as well, but in contrast to serum mainly when added to the apical side of PBCEC. Addition of VEGF caused a serum-like decrease of the TER with the same polar effect; however, VEGF will be denatured by heat and could thus not be the heat-sensitive factor. Thus, we hypothesise that serum contains a variety of factors which weaken the tightness of a PBCEC monolayer from the apical side as expected but also from the basolateral side. Although the structure of the 67 kDa factor could not be analysed, this finding is of importance for in vitro models not only of the blood-brain barrier mostly using serum-containing media.

Animals↗
PubMed1988

An electron microscope study of the development of the exocrine and endocrine pancreas with special reference to intercellular junctions.

Intercellular junctions in pancreatic acinar, duct and endocrine cells were studied by thin section and freeze-fracture methods in developing rats and mice. Undifferentiated cells were joined by the zonula occludens and isolated fragments of tight junctional strands. Small gap junctions were either occasionally associated with tight junctional strands or appeared independent of them. During the morphological differentiation of acinar cells, strands of the zonula occludens developed to form a complicated meshwork while gap junctions rapidly increased in size. Duct cells were joined by the less-developed zonula occludens but gap junctions were rarely seen. In the neonate, intercellular junctions were similar to those in adult acini and intercalated ducts. Endocrine cells were joined by maculae occludentes and small gap junctions. During late prenatal days, the macula occludens increased in size and gap junctions in number. Sometimes tight junctional strands disappeared to leave membrane elevations, some of which were associated with small gap junctions. Maculae occludentes on endocrine cells were gradually fragmentized and diminished during postnatal development. They were completely lost in the rat. These results suggest that intercellular junctions play important roles in pancreatic development. In particular, the transient development of maculae occludentes is associated with endocrine cell development, and intercellular communication mediated by gap junctions may be important for the differentiation of acinar and endocrine cells.

Animals↗
PubMed2006

TRPV4-mediated regulation of epithelial permeability.

TRPV4 is a calcium-permeable channel activated by extracellular hypotonicity, polyunsaturated fatty acids, phorbol esters, and heat. We show that TRPV4 is localized in the basolateral membrane of the mouse mammary cell line HC11. Activation of TRPV4 caused an increase in the intracellular Ca(2+) concentration through influx of extracellular Ca(2+), triggering two independent chains of events: 1) a rapid increase in transcellular conductance through the activation of apical large conductance calcium-activated (BK) potassium channels that were blockable by paxilline; 2) a slow increase in paracellular permeability for small solutes. The latter effect was accompanied by a down-regulation of the tight junctional proteins claudin -1, -3, -4, -5, -7, and -8 and by dramatic changes in tight junction morphology, including frequent large breaks in the tight junction strands. This dual modulation of epithelial permeability after TRPV4 activation may be involved in regulating the tonicity across mammary gland epithelia. TRPV4 activation may also be responsible for exudation and edema formation during inflammation processes.-Reiter, B., Kraft, R., Günzel, D., Zeissig, S., Schulzke, J-D., Fromm, M., Harteneck, C. TRPV4-mediated regulation of epithelial permeability.

Animals↗