Transmembrane proteins of the tight junctions at the blood–brain barrier: Structural and functional aspects

Haseloff, Reiner F.; Dithmer, Sophie; Winkler, Lars; Wolburg, Hartwig; Blasig, Ingolf E.

doi:10.1016/j.semcdb.2014.11.004

Cited by 282 publications

(216 citation statements)

References 126 publications

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“…While CLDN5 is highly expressed in the brain endothelium, CLDN1 expression in cerebral capillaries is low and was only confirmed to be present in human, rat, and sheep BBB 3, 30, 31. Regardless of the low expression, CLDN1 function in human brain capillaries is critical for the maintenance of the BBB integrity during neuroinflammation and brain tumor 29, 44.…”

Section: Discussionmentioning

confidence: 99%

“…Passive diffusion through the BBB is regulated by brain endothelial tight junctions (TJs), which are composed of transmembrane and cytosolic TJ‐associated protein complexes 1, 2. Among major TJ proteins, which play a critical role in the formation and integrity of vascular barrier are occludin, claudins (claudin‐5 [CLDN5] and claudin‐1 [CLDN1], among other family members), and a major scaffolding protein ZO‐1 (member of the zonula occludens protein family) 3, 4. Expression, cellular distribution, and interaction of these proteins with each other are critical for paracellular permeability and TJ‐mediated signaling 5.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…These are typically composed of two similar opposing layers of interacting proteins embedded as oligomers or arrays in the cellular membranes. For example, paired arrays of cadherins are found in adherens junctions and desmosomes (1); of claudins and occludins in tight junctions (2,3); and of connexin channels in gap junctions (4). The back-to-back architecture of these junctions is fundamental to their adhesive function.…”

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confidence: 99%

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Tolun

Vijayasarathy

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Retinoschisin (RS1) is involved in cell-cell junctions in the retina, but is unique among known cell-adhesion proteins in that it is a soluble secreted protein. Loss-of-function mutations in RS1 lead to early vision impairment in young males, called X-linked retinoschisis. The disease is characterized by separation of inner retinal layers and disruption of synaptic signaling. Using cryo-electron microscopy, we report the structure at 4.1 Å, revealing double octamer rings not observed before. Each subunit is composed of a discoidin domain and a small N-terminal (RS1) domain. The RS1 domains occupy the centers of the rings, but are not required for ring formation and are less clearly defined, suggesting mobility. We determined the structure of the discoidin rings, consistent with known intramolecular and intermolecular disulfides. The interfaces internal to and between rings feature residues implicated in X-linked retinoschisis, indicating the importance of correct assembly. Based on this structure, we propose that RS1 couples neighboring membranes together through octamer-octamer contacts, perhaps modulated by interactions with other membrane components.retinoschisin | X-linked retinoschisis | discoidin domain | cryo-electron microscopy | single particle analysis T he structural integrity and functioning of tissues are highly dependent on cell-cell junctions. These are typically composed of two similar opposing layers of interacting proteins embedded as oligomers or arrays in the cellular membranes. For example, paired arrays of cadherins are found in adherens junctions and desmosomes (1); of claudins and occludins in tight junctions (2, 3); and of connexin channels in gap junctions (4). The back-to-back architecture of these junctions is fundamental to their adhesive function.The retina features another protein implicated in cell-cell adhesion, retinoschisin (RS1). RS1 is a 24-kDa protein expressed exclusively by photoreceptors and bipolar cells in the retina (5) and pineal gland (6). Loss-of-function mutants of RS1 lead to progressive visual impairment in a disease called X-linked retinoschisis (XLRS) (7-9). The clinical manifestation is a pathological separation of retinal layers, leading to structural splitting and cavity (or "schisis") formation (10). Additionally, the bipolar cells show disorganization (11) and failure to maintain synaptic organization (9). Both XLRS patients and RS1 gene knockout mouse models (Rs1-KO) show similar phenotypes: schisis/splitting through retinal layers and synaptic transmission defects manifested as reduced b-wave amplitudes on the clinical electroretinogram ( Fig. S1) (8, 12). RS1 gene therapy rescues the XLRS mouse phenotype (9, 13) and human RS1 gene therapy trials are underway (ClinicalTrials.gov: NCT02317887; NCT02416622).RS1 is secreted as a soluble disulfide bond-stabilized octamer (14, 15). Most of the monomer comprises a discoidin (DS) domain, a globular fold that is highly conserved over many proteins with diverse functions (16). Little progress has been made toward...

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“…[7][8][9] The BBB restricts various therapeutic agents to enter the CNS. [9][10][11] According to the general principle, to maximize drug efficacy, the drug should be absorbed and then distributed efficiently to the affected sites. Developing drug delivery strategies across the BBB is important for therapeutic agents to enter the CNS.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg1 nanoparticle penetrating the blood–brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction

Shen¹,

Zhao²,

Wang³

et al. 2017

IJN

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Diabetic cerebral infarction is with poorer prognosis and high rates of mortality. Ginsenoside Rg1 (Rg1) has a wide variety of therapeutic values for central nervous system (CNS) diseases for the neuron protective effects. However, the blood–brain barrier (BBB) restricts Rg1 in reaching the CNS. In this study, we investigated the therapeutic effects of Rg1 nanoparticle (PHRO, fabricated with γ-PGA, L-PAE (H), Rg1, and OX26 antibody), targeting transferrin receptor, on the diabetes rats complicated with diabetic cerebral infarction in vitro and in vivo. Dynamic light scattering analysis shows the average particle size of PHRO was 79±18 nm and the polydispersity index =0.18. The transmission electron microscope images showed that all NPs were spherical in shape with diameters of 89±23 nm. PHRO released Rg1 with sustained release manner and could promote the migration of cerebrovascular endothelial cells and tube formation and even penetrated the BBB in vitro. PHRO could penetrate the BBB with high concentration in brain tissue to reduce the cerebral infarction volume and promote neuronal recovery in vivo. PHRO was promising to be a clinical treatment of diabetes mellitus with cerebral infarction.

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Transmembrane proteins of the tight junctions at the blood–brain barrier: Structural and functional aspects

Cited by 282 publications

References 126 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Ginsenoside Rg1 nanoparticle penetrating the blood–brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction

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Transmembrane proteins of the tight junctions at the blood–brain barrier: Structural and functional aspects

Cited by 282 publications

References 126 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Ginsenoside Rg1 nanoparticle penetrating the blood&ndash;brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction

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Ginsenoside Rg1 nanoparticle penetrating the blood–brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction