Unexpected Roles of the Na-K-ATPase and Other Ion Transporters in Cell Junctions and Tubulogenesis

Physiology ◽  
2009 ◽  
Vol 24 (3) ◽  
pp. 192-201 ◽  
Author(s):  
Thomas Krupinski ◽  
Greg J. Beitel
Keyword(s):  
Ion Transport ◽  
Intercellular Junctions ◽  
Cell Junctions ◽  
Ion Pumps ◽  
Ion Transporters ◽  
C Elegans ◽  
Independent Functions ◽  
Junctional Complexes ◽  
And Control ◽  
Epithelial Tubes

Recent work shows that transport-independent as well as transport-dependent functions of ion transporters, and in particular the Na-K-ATPase, are required for formation and maintenance of several intercellular junctions. Furthermore, these junctional and other nonjunctional functions of ion transporters contribute to development of epithelial tubes. Here, we consider what has been learned about the roles of ion pumps in formation of junctions and epithelial tubes in mammals, zebrafish, Drosophila, and C. elegans. We propose that asymmetric association of the Na-K-ATPase with cell junctions early in metazoan evolution enabled vectorial transcellular ion transport and control of intraorganismal environment. Ion transport-independent functions of the Na-K-ATPase arose as junctional complexes evolved.

scholarly journals Plectin ensures intestinal epithelial integrity and protects colon against colitis

2021 ◽  
Vol 14 (3) ◽  
pp. 691-702
Author(s):  
Alzbeta Krausova ◽  
Petra Buresova ◽  
Lenka Sarnova ◽  
Gizem Oyman-Eyrilmez ◽  
Jozef Skarda ◽  
...  
Keyword(s):  
Mechanical Stability ◽  
Intestinal Barrier ◽  
Intercellular Junctions ◽  
Protein Profiling ◽  
Cell Junctions ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Critical Determinant ◽  
In Vitro Feeding

AbstractPlectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; PleΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.

Increased Tyr phosphorylation of ZO-1 during modification of tight junctions between glomerular foot processes

1995 ◽  
Vol 268 (3) ◽  
pp. F514-F524 ◽  
Author(s):  
H. Kurihara ◽  
J. M. Anderson ◽  
M. G. Farquhar
Keyword(s):  
Tight Junction ◽  
Tyrosine Phosphorylation ◽  
Tight Junctions ◽  
Mesangial Cells ◽  
Basal Membrane ◽  
Cell Junctions ◽  
Phosphorylated Proteins ◽  
Cell Matrix ◽  
Rapid Changes ◽  
And Control

The slit diaphragms between the glomerular epithelial foot processes represent a variant of the tight junction that are rapidly replaced by typical tight junctions after perfusion with protamine sulfate (PS). To investigate the mechanism of signaling involved, tyrosine phosphorylation of glomerular proteins was analyzed in newborn, PS-treated, and control rats using antiphosphotyrosine immunoglobulin G. In glomeruli of normal adults, phosphotyrosine (Ptyr) staining was confined largely to mesangial cells by immunofluorescence, whereas in newborn and PS-treated rats, the Ptyr signal was dramatically increased in the glomerular epithelium. By immunogold labeling, it was found that newly phosphorylated proteins were concentrated along the newly formed tight junctions (cell-cell junctions) and the basal membrane of the foot processes (cell-matrix junctions). By immunoblotting, several prominent bands were detected with anti-Ptyr in glomerular lysates of controls; in PS-treated rats, additional bands were detected at 225, 180, and 100 kDa. The 225-kDa protein was identified as ZO-1 by immunoprecipitation with anti-ZO-1 followed by immunoblotting with anti-Ptyr. These findings indicate that ZO-1 is one of the targets for tyrosine phosphorylation after PS treatment. They indicate that phosphorylation of tight junction and other proteins occurs during the formation of tight junctions in glomeruli under circumstances where there are rapid changes in epithelial cell shape.

scholarly journals Luqin-like RYamide peptides regulate food-evoked responses in C. elegans

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Hayao Ohno ◽  
Morikatsu Yoshida ◽  
Takahiro Sato ◽  
Johji Kato ◽  
Mikiya Miyazato ◽  
...  
Keyword(s):  
Critical Role ◽  
Egg Laying ◽  
Serotonergic Neuron ◽  
Pacemaker Neurons ◽  
C Elegans ◽  
Peptide Signaling ◽  
Multiple Organs ◽  
Locomotory Behavior ◽  
Control Food ◽  
And Control

Peptide signaling controls many processes involving coordinated actions of multiple organs, such as hormone-mediated appetite regulation. However, the extent to which the mode of action of peptide signaling is conserved in different animals is largely unknown, because many peptides and receptors remain orphan and many undiscovered peptides still exist. Here, we identify two novel Caenorhabditis elegans neuropeptides, LURY-1-1 and LURY-1-2, as endogenous ligands for the neuropeptide receptor-22 (NPR-22). Both peptides derive from the same precursor that is orthologous to invertebrate luqin/arginine-tyrosine-NH2 (RYamide) proneuropeptides. LURY-1 peptides are secreted from two classes of pharyngeal neurons and control food-related processes: feeding, lifespan, egg-laying, and locomotory behavior. We propose that LURY-1 peptides transmit food signals to NPR-22 expressed in feeding pacemaker neurons and a serotonergic neuron. Our results identified a critical role for luqin-like RYamides in feeding-related processes and suggested that peptide-mediated negative feedback is important for satiety regulation in C. elegans.

scholarly journals Targeting Cancer Cell Tight Junctions Enhances PLGA-Based Photothermal Sensitizers’ Performance In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 43
Author(s):  
Victoria O. Shipunova ◽  
Vera L. Kovalenko ◽  
Polina A. Kotelnikova ◽  
Anna S. Sogomonyan ◽  
Olga N. Shilova ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
3D Culture ◽  
Intercellular Junctions ◽  
Cell Junctions ◽  
Multicellular Spheroids ◽  
Mesenchymal Transition ◽  
Non Invasive ◽  
Order Of Magnitude

The development of non-invasive photothermal therapy (PTT) methods utilizing nanoparticles as sensitizers is one of the most promising directions in modern oncology. Nanoparticles loaded with photothermal dyes are capable of delivering a sufficient amount of a therapeutic substance and releasing it with the desired kinetics in vivo. However, the effectiveness of oncotherapy methods, including PTT, is often limited due to poor penetration of sensitizers into the tumor, especially into solid tumors of epithelial origin characterized by tight cellular junctions. In this work, we synthesized 200 nm nanoparticles from the biocompatible copolymer of lactic and glycolic acid, PLGA, loaded with magnesium phthalocyanine, PLGA/Pht-Mg. The PLGA/Pht-Mg particles under the irradiation with NIR light (808 nm), heat the surrounding solution by 40 °C. The effectiveness of using such particles for cancer cells elimination was demonstrated in 2D culture in vitro and in our original 3D model with multicellular spheroids possessing tight cell contacts. It was shown that the mean inhibitory concentration of such nanoparticles upon light irradiation for 15 min worsens by more than an order of magnitude: IC50 increases from 3 µg/mL for 2D culture vs. 117 µg/mL for 3D culture. However, when using the JO-4 intercellular junction opener protein, which causes a short epithelial–mesenchymal transition and transiently opens intercellular junctions in epithelial cells, the efficiency of nanoparticles in 3D culture was comparable or even outperforming that for 2D (IC50 = 1.9 µg/mL with JO-4). Synergy in the co-administration of PTT nanosensitizers and JO-4 protein was found to retain in vivo using orthotopic tumors of BALB/c mice: we demonstrated that the efficiency in the delivery of such nanoparticles to the tumor is 2.5 times increased when PLGA/Pht-Mg nanoparticles are administered together with JO-4. Thus the targeting the tumor cell junctions can significantly increase the performance of PTT nanosensitizers.

scholarly journals The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses in C. elegans

2021 ◽  
Author(s):  
Bhoomi Madhu ◽  
Tina L. Gumienny
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Defense Responses ◽  
C Elegans ◽  
Host Immune Responses ◽  
Wide Range ◽  
Independent Functions ◽  
Multiple Cell

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

scholarly journals Tracking Epithelial Cell Junctions in C. elegans Embryogenesis With Active Contours Guided by SIFT Flow

2015 ◽  
Vol 62 (4) ◽  
pp. 1020-1033 ◽  
Author(s):  
Sukryool Kang ◽  
Chen-Yu Lee ◽  
Monira Goncalves ◽  
Andrew D. Chisholm ◽  
Pamela C. Cosman
Keyword(s):  
Epithelial Cell ◽  
Active Contours ◽  
Cell Junctions ◽  
C Elegans ◽  
Sift Flow

Cell junctions in the developing compound eye of the desert locust Schistocerca gregaria

Development ◽  
1976 ◽  
Vol 36 (2) ◽  
pp. 409-423
Author(s):  
S. Eley ◽  
P. M. J. Shelton
Keyword(s):  
Gap Junctions ◽  
Compound Eye ◽  
Schistocerca Gregaria ◽  
Intercellular Junctions ◽  
Cell Junctions ◽  
Different Types ◽  
Undifferentiated Cells ◽  
Development Gap ◽  
Sequential Appearance ◽  
Subsequent Disappearance

Intercellular junctions in the developing retina of the locust Schistocerca gregaria have been examined by electron microscopy. Different types of junction appear in a well-defined sequence during development. Five stages of ommatidial development are described. Close junctions and punctate junctions are present throughout development. Gap junctions appear transiently amongst the undifferentiated cells, before clearly defined preommatidia can be distinguished. The subsequent disappearance of gap junctions may be correlated with cell determination. Lanthanum studies confirm these findings. The later sequential appearance of adhesive junction types is described. These include septate desmosomes and two types of desmosomes. In the fully differentiated ommatidium only two types of junction remain, these are: desmosomes and rhabdomeric junctions.

Vascular Biology, Thromboresistance, and Inflammation

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
Endothelial Cells ◽  
Cardiovascular System ◽  
Vascular Endothelium ◽  
Vascular Endothelial Cells ◽  
Surface Membrane ◽  
Single Layer ◽  
Intercellular Junctions ◽  
Cell Junctions ◽  
Luminal Surface ◽  
Internal Layers

The delivery of vital substrate to metabolically active tissues and vital organs is achieved and maintained by the cardiovascular system including the heart, macrovasculature, and microvasculature. This life-sustaining process requires a normally functioning vascular endothelium—a multifunctional organ system composed of physiologically responsive cells responsible for vasomotion (vascular tone), thromboresistance, and inflammoresistance. Simply by virtue of its anatomic location, the vascular endothelium is functionally complex. It defines the intra- and extravascular components, serves as a selectively permeable barrier, and provides a continuous lining to the cardiovascular system. The location of the vascular endothelium is vital to its biologic interactions with cells found within the circulation and to the vessel wall itself. The surface activity is augmented in the microcirculation, also known as the resistance bed, where the ratio of endothelial surface to circulating blood is maximal. In most vertebrates, vascular endothelial cells form a single layer of squamous lining cells (0.1–0.5 μm in thickness) joined by intercellular junctions. The cells themselves are polygonal (varying between 10 and 50 μm) and are positioned in the long axis of the vessel, orienting the cellular longitudinal dimension in the direction of blood flow. The endothelial cell has three surfaces: luminal (nonthrombogenic), subluminal (adhesive), and cohesive. The luminal surface is devoid of electron-dense connective tissue. It does, however, possess an exterior coat (or glycocalyx), consisting primarily of starches and proteins secreted by the endothelial cells. Plasma proteins, including lipoprotein lipase, α2-macroglobulin, heparin cofactor II, antithrombin, and albumin, as well as small amounts of fibrinogen and fibrin are adsorbed to the luminal surface. The surface membrane itself adds significantly to thromboresistance by carrying a negative charge that repels similarly charged circulating blood cells. The subluminal (or abluminal) surface adheres to subendothelial connective tissues. Small processes penetrate through a series of internal layers to form myoendothelial junctions with subjacent smooth muscle cells. The cohesive component of the vascular endothelium connects individual endothelial cells to one another by cell junctions of two basic types: occluding (tight) junctions and communicating (gap) junctions. Occluding junctions represent a physical link between adjacent cells, sealing the intercellular space.

scholarly journals Calcineurin inhibits VCX1-dependent H+/Ca2+ exchange and induces Ca2+ ATPases in Saccharomyces cerevisiae.

1996 ◽  
Vol 16 (5) ◽  
pp. 2226-2237 ◽  
Author(s):  
K W Cunningham ◽  
G R Fink
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Phosphatase ◽  
Reporter Genes ◽  
Immunosuppressive Drug ◽  
Ion Pumps ◽  
Ion Transporters ◽  
Lacz Reporter ◽  
Dependent Protein ◽  
P Type ◽  
Calcineurin Activity

The PMC1 gene in Saccharomyces cerevisiae encodes a vacuolar Ca2+ ATPase required for growth in high-Ca2+ conditions. Previous work showed that Ca2+ tolerance can be restored to pmc1 mutants by inactivation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase sensitive to the immunosuppressive drug FK506. We now report that calcineurin decreases Ca2+ tolerance of pmc1 mutants by inhibiting the function of VCX1, which encodes a vacuolar H+/Ca2+ exchanger related to vertebrate Na+/Ca2+ exchangers. The contribution of VCX1 in Ca2+ tolerance is low in strains with a functional calcineurin and is high in strains which lack calcineurin activity. In contrast, the contribution of PMC1 to Ca2+ tolerance is augmented by calcineurin activation. Consistent with these positive and negative roles of calcineurin, expression of a vcx1::lacZ reporter was slightly diminished and a pmc1::lacZ reporter was induced up to 500-fold by processes dependent on calcineurin, calmodulin, and Ca2+. It is likely that calcineurin inhibits VCX1 function mainly by posttranslational mechanisms. Activities of VCX1 and PMC1 help to control cytosolic free Ca2+ concentrations because their function can decrease pmc1::lacZ induction by calcineurin. Additional studies with reporter genes and mutants indicate that PMR1 and PMR2A, encoding P-type ion pumps required for Mn2+ and Na+ tolerance, may also be induced physiologically in response to high-Mn2+ and -Na+ conditions through calcineurin-dependent mechanisms. In these situations, inhibition of VCX1 function may be important for the production of Ca2+ signals. We propose that elevated cytosolic free Ca2+ concentrations, calmodulin, and calcineurin regulate at least four ion transporters in S. cerevisiae in response to several environmental conditions.

scholarly journals Uremia Impacts VE-Cadherin and ZO-1 Expression in Human Endothelial Cell-to-Cell Junctions

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 404 ◽  
Author(s):  
Rayana Maciel ◽  
Regiane Cunha ◽  
Valentina Busato ◽  
Célia Franco ◽  
Paulo Gregório ◽  
...  
Keyword(s):  
Protein Expression ◽  
Intercellular Junctions ◽  
Serum Levels ◽  
Endothelial Damage ◽  
Cell Junctions ◽  
Cell Junction ◽  
Uremic Serum ◽  
Gene And Protein Expression ◽  
The Impact

Endothelial dysfunction in uremia can result in cell-to-cell junction loss and increased permeability, contributing to cardiovascular diseases (CVD) development. This study evaluated the impact of the uremic milieu on endothelial morphology and cell junction’s proteins. We evaluated (i) serum levels of inflammatory biomarkers in a cohort of chronic kidney disease (CKD) patients and the expression of VE-cadherin and Zonula Occludens-1 (ZO-1) junction proteins on endothelial cells (ECs) of arteries removed from CKD patients during renal transplant; (ii) ECs morphology in vitro under different uremic conditions, and (iii) the impact of uremic toxins p-cresyl sulfate (PCS), indoxyl sulfate (IS), and inorganic phosphate (Pi) as well as of total uremic serum on VE-cadherin and ZO-1 gene and protein expression in cultured ECs. We found that the uremic arteries had lost their intact and continuous endothelial morphology, with a reduction in VE-cadherin and ZO-1 expression. In cultured ECs, both VE-cadherin and ZO-1 protein expression decreased, mainly after exposure to Pi and uremic serum groups. VE-cadherin mRNA expression was reduced while ZO-1 was increased after exposure to PCS, IS, Pi, and uremic serum. Our findings show that uremia alters cell-to-cell junctions leading to an increased endothelial damage. This gives a new perspective regarding the pathophysiological role of uremia in intercellular junctions and opens new avenues to improve cardiovascular outcomes in CKD patients.

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