Interplay between tight junctions &amp; adherens junctions

Campbell, Hannah; Maiers, Jessica L.; DeMali, Kris A.

doi:10.1016/j.yexcr.2017.03.061

Cited by 259 publications

(215 citation statements)

References 65 publications

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“…In general, cell–cell adhesion via adherens and tight junctions where Cx36 plaques are localized is mediated by occludins, cadherins and nectins, which recruit zonula occludin 1 (ZO1), α‐ and β‐catenin and AF6, respectively, to the plasma membrane (Segretain & Falk, ; Campbell et al . ). As ZO1 has been shown to colocalize with Cx36 in several cell types (Giepmans, ; Li et al .…”

Section: Discussionmentioning

confidence: 97%

“…Epac2 regulation of gap junction turnover likely occurs via Ras-related protein 1 (Rap1) activation of afadin (AF6), which colocalizes with Cx36. [Colour figure can be viewed at wileyonlinelibrary.com] J Physiol 597.2 recruit zonula occludin 1 (ZO1), αand β-catenin and AF6, respectively, to the plasma membrane (Segretain & Falk, 2004;Campbell et al 2017). As ZO1 has been shown to colocalize with Cx36 in several cell types (Giepmans, 2004;Li et al 2004), AF6 may also be present at these junctions in the β-cell and could mediate Epac2 regulation of Cx36 turnover.…”

Section: Gap Junction Assemblymentioning

confidence: 99%

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Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Farnsworth

Walter

Piscopio

et al. 2018

The Journal of Physiology

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Key points The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca2+ signalling and electrical coupling of the insulin producing β‐cells in the islet. We have previously shown that cytokines decrease β‐cell coupling and that compounds which increase cAMP can increase coupling. In both mouse and human islets exendin‐4, which increases cAMP, protected against cytokine‐induced decreases in coupling and in mouse islets preserved glucose‐stimulated calcium signalling by increasing connexin36 gap junction levels on the plasma membrane. Our data indicate that protein kinase A regulates β‐cell coupling through a fast mechanism, such as channel gating or membrane organization, while Epac2 regulates slower mechanisms of regulation, such as gap junction turnover. Increases in β‐cell coupling with exendin‐4 may protect against cytokine‐mediated β‐cell death as well as preserve insulin secretion dynamics during the development of diabetes. Abstract The pancreatic islets of Langerhans maintain glucose homeostasis. Insulin secretion from islet β‐cells is driven by glucose metabolism, depolarization of the cell membrane and an influx of calcium, which initiates the release of insulin. Gap junctions composed of connexin36 (Cx36) electrically couple β‐cells, regulating calcium signalling and insulin secretion dynamics. Cx36 coupling is decreased in pre‐diabetic mice, suggesting a role for altered coupling in diabetes. Our previous work has shown that pro‐inflammatory cytokines decrease Cx36 coupling and that compounds which increase cAMP can increase Cx36 coupling. The goal of this study was to determine if exendin‐4, which increases cAMP, can protect against cytokine‐induced decreases in Cx36 coupling and altered islet function. In both mouse and human islets, exendin‐4 protected against cytokine‐induced decreases in coupling and preserved glucose‐stimulated calcium signalling. Exendin‐4 also protected against protein kinase Cδ‐mediated decreases in Cx36 coupling. Exendin‐4 preserved coupling in mouse islets by preserving Cx36 levels on the plasma membrane. Exendin‐4 regulated Cx36 coupling via both protein kinase A (PKA)‐ and Epac2‐mediated mechanisms in cytokine‐treated islets. In mouse islets, modulating Epac2 had a greater impact in mediating Cx36 coupling, while in human islets modulating PKA had a greater impact on Cx36 coupling. Our data indicate that PKA regulates Cx36 coupling through a fast mechanism, such as channel gating, while Epac2 regulates slower mechanisms of regulation, such as Cx36 turnover in the membrane. Increases in Cx36 coupling with exendin‐4 may protect against cytokine‐mediated β‐cell dysfunction to insulin secretion dynamics during the development of diabetes.

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Section: Discussionmentioning

confidence: 97%

Section: Gap Junction Assemblymentioning

confidence: 99%

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Farnsworth

Walter

Piscopio

et al. 2018

The Journal of Physiology

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“…Although adherens and tight junctions are formed by distinct structural proteins, with specific binding affinities, the assembly of tight junctions has been demonstrated as coupled with the formation of adherens junctions. Physical linkages between these junctional structures can be mediated by a multistep process that involves α–, β-catenins, ZO-1 and afadin proteins interactions, initiating with adherens junctions protein clustering and structural organization on cell membranes that later recruit and allow tight junctional machinery to assemble (for revision Campbell et al, 2017). In fact, β-catenin/FoxO1 transcription factor complex was demonstrated to repress Claudin-5 tight junction gene expression (Taddei et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Adesse

Marcos

Siqueira

et al. 2018

Preprint

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Congenital toxoplasmosis is a parasitic disease that occurs due vertical transmission of the protozoan Toxoplasma gondii (T. gondii) during pregnancy. The parasite crosses the placental barrier and reaches the developing brain, infecting progenitor, glial, neuronal and vascular cell types. Although the role of Radial glia (RG) neural stem cells in the development of the brain vasculature has been recently investigated, the impact of T. gondii infection in these events is not yet understood. Herein, we studied the role of T. gondii infection on RG cell function and its interaction with endothelial cells. By infecting isolated RG cells with T. gondii tachyzoites, we observed reduced cell proliferation and neurogenesis without affecting gliogenesis levels. Conditioned medium (CM) from RG control cultures increased ZO-1 and β-catenin protein levels and organization on endothelial bEnd.3 cells membranes, which was completely impaired by CM from infected RG, resulting in decreased transendothelial electrical resistance (TEER). Cytokine Bead Array and ELISA assays revealed the presence of increased levels of the pro-inflammatory cytokine IL-6 and reduced levels of anti-inflammatory cytokine TGF-β1 in CM from T.gondii-infected RG cells. Treatment with recombinant TGF-β1 concomitantly with CM from infected RG cultures led to restoration of ZO-1 staining in bEnd.3 cells. Our results suggest that infection of RG cells by T. gondii modulate cytokine secretion, which might contribute to endothelial loss of barrier properties, thus leading to impairment of neurovascular interaction establishment.

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“…Cell-cell junction BBB properties are primarily determined by BMEC AJs and TJs. Cell-cell AJ junction offers contracting force to bridge adjacent ECs via cadherins and nectins [93]. It physically interacts with TJs and indirectly links to TJ via actin-associated proteins [88,93].…”

Section: Whole-brain Lysate Proteomic Functional Groupmentioning

confidence: 99%

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Chang

Drelich

et al. 2019

Preprint

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Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs.Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more susceptible to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endosomes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified 2 several relevant cell-cell junction functions. Immunohistology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Similar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated tight junctions and its role in stabilizing the BBB in these deadly infections. Author SummaryTraditionally, spontaneous intracerebral microhemorrhages (CMHs) were defined as small foci of intracerebral hemorrhages. Such atraumatic CMHs are due to the rupture of a weak blood vessel wall. Infections complicating cerebrovascular accidents have been extensively investigated.However, the role of CMHs complicating infections, in particularly acute systemic infections, has been poorly explored. Population-based retrospective cohort studies suggest there are potentially more undiscovered cases of CMHs accompanying acute systemic infections. Given both the lack of an animal model and cellular/molecular pathophysiology of CMHs following acute systemic infections, there is an urgent need to increase our comprehensive understanding of acute infectioninduced CMHs. Overall, our study revealed a novel role of annexin a2 (ANXA2) in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated endothelial tight junctions and its role in stabilizing the bloodbrain barrier in these deadly infections.

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Interplay between tight junctions & adherens junctions

Cited by 259 publications

References 65 publications

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

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