SnapShot: Connexins and Disease

Laird, Dale W.; Naus, Christian C.; Lampe, Paul D.

doi:10.1016/j.cell.2017.08.034

Cited by 46 publications

(52 citation statements)

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“…S1). Moreover, a number of disease-causing mutations in various connexins are found in the conserved Ca 2+ -binding tunnel (35). These data strongly suggest that intact Ca 2+ -binding tunnels are functionally crucial for most connexin family members.…”

Section: The Hemichannel Structure In the Presence Of Calcium Ions Rementioning

confidence: 88%

Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel

et al. 2020

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Connexin family proteins assemble into hexameric channels called hemichannels/connexons, which function as transmembrane channels or dock together to form gap junction intercellular channels (GJIChs). We determined the cryo–electron microscopy structures of human connexin 31.3 (Cx31.3)/GJC3 hemichannels in the presence and absence of calcium ions and with a hearing-loss mutation R15G at 2.3-, 2.5-, and 2.6-Å resolutions, respectively. Compared with available structures of GJICh in open conformation, Cx31.3 hemichannel shows substantial structural changes of highly conserved regions in the connexin family, including opening of calcium ion–binding tunnels, reorganization of salt-bridge networks, exposure of lipid-binding sites, and collocation of amino-terminal helices at the cytoplasmic entrance. We also found that the hemichannel has a pore with a diameter of ~8 Å and selectively transports chloride ions. Our study provides structural insights into the permeant selectivity of Cx31.3 hemichannel.

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Section: The Hemichannel Structure In the Presence Of Calcium Ions Rementioning

confidence: 88%

Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel

et al. 2020

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“…This is in keeping with previous studies suggesting that the Panx1-Gly2 is the predominant post-translationally modified form of Panx1 in the plasma membrane that forms hexameric membrane-channels (Boassa et al, 2007; Penuela et al, 2007). Pannexins are close family members of the connexin protein family which have a protein half-life of between 1-4 hours (Laird, 2006; Laird et al, 2017). An interesting observation in our study was that, once at the plasma membrane, the Panx1-Gly2 isoform is highly stable, unlike Cx43, and may persist for several days after the removal of TNF.…”

Section: Discussionmentioning

confidence: 99%

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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25inflammation, endothelial cell, smooth muscle cell 4 to prolonged tumor necrosis factor alpha (TNF) treatment, Yang et al. found that the Panx1 5 channel is targeted to the plasma membrane, where it facilitates an increase in intracellular 6 calcium to control the production and release of cytokines including IL-1β. 7 8 GRAPHICAL ABSTRACT 9 10 Graphical Abstract: The inflammatory process in endothelial cells is controlled by Ca 2+ entry through Pannexin 1 membrane channels. 3 Abstract 1The proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease 2 that can be targeted to reduce major cardiovascular events. IL-1β expression and release 3 are tightly controlled by changes in intracellular Ca 2+ . In addition, purinergic signaling 4 through ATP release has also been reported to promote IL-1β production. Despite this, 5 the mechanisms that control IL-1β synthesis and expression have not been identified. 6The pannexin 1 (Panx1) channel has canonically been implicated in ATP release, 7 especially during inflammation. However, resolution of purinergic signaling occurs quickly 8 due to blood flow and the presence of ectonucleotidases. We examined Panx1 in human 9 endothelial cells following treatment with the pro-inflammatory cytokine tumor necrosis 10 alpha (TNF). In response to long-term TNF treatment, we identified a dramatic increase 11 in Panx1 protein expression at the plasma membrane. Analysis by whole transcriptome 12 sequencing (RNA-seq), qPCR, and treatment with specific kinase inhibitors, revealed that 13 TNF signaling induced NFκβ-associated Panx1 transcription. Genetic inhibition of Panx1 14 reduced the expression and secretion of IL-1β. We initially hypothesized that increased 15Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. 16However, our data demonstrate that IL1-β expression was not altered after direct ATP 17 stimulation, following degradation of ATP by apyrase, or after pharmacological blockade 18 of P2 receptors. These data suggest that non-purinergic pathways, involving Panx1, 19 control IL-1β production. Because Panx1 forms a large pore channel, we hypothesized it 20 may act to passively diffuse Ca 2+ into the cell upon opening to regulate IL-1β. High-21 throughput flow cytometric analysis demonstrated that TNF treatments lead to elevated 22 intracellular Ca 2+ . Genetic or pharmacological inhibition of Panx1 reduced TNF-23 associated increases in intracellular Ca 2+ , and IL-1β transcription. Furthermore, we found 24 that the Ca 2+ -sensitive NFκβ-p65 protein failed to localize to the nucleus after genetic or 25 pharmacological block of Panx1. Taken together, our study provides the first evidence 26 that intracellular Ca 2+ regulation via the Panx1 channel induces a feed-forward effect on 27NFκβ to regulate IL-1β synthesis and release in endothelium during inflammation. 28 4 (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates

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“…Dysregulation of connexin expression in the epidermis is associated with a variety of conditions, re-enforcing the importance of these proteins in maintaining epidermal integrity. This is most evident for Cx43 and Cx26 where alteration in the fine balance of control of expression is associated with pathological conditions including chronic non-healing wounds, psoriasis and a range of connexin-channelopathies linked with mutations in β-connexins causing skin disease [ 8 , 51 ].…”

Section: Connexins In the Epidermismentioning

confidence: 99%

“…Thus, the pattern in which these proteins are expressed is very important to cellular function, with each combination of heteromeric channel conferring unique signalling properties. Heterotypic channels are limited in function by connexin compatibility, predicted to prevent cells following different differential pathways to ‘communicate’ [ 8 ]. Connexins have a short half-life, resulting in rapid turnover and, together, these properties enable specialised tissue-specific, spatial and temporal communication compartments.…”

Section: Introductionmentioning

confidence: 99%

Connexin Communication Compartments and Wound Repair in Epithelial Tissue

Chanson

Watanabe

O'Shaughnessy

et al. 2018

IJMS

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Epithelial tissues line the lumen of tracts and ducts connecting to the external environment. They are critical in forming an interface between the internal and external environment and, following assault from environmental factors and pathogens, they must rapidly repair to maintain cellular homeostasis. These tissue networks, that range from a single cell layer, such as in airway epithelium, to highly stratified and differentiated epithelial surfaces, such as the epidermis, are held together by a junctional nexus of proteins including adherens, tight and gap junctions, often forming unique and localised communication compartments activated for localised tissue repair. This review focuses on the dynamic changes that occur in connexins, the constituent proteins of the intercellular gap junction channel, during wound-healing processes and in localised inflammation, with an emphasis on the lung and skin. Current developments in targeting connexins as corrective therapies to improve wound closure and resolve localised inflammation are also discussed. Finally, we consider the emergence of the zebrafish as a concerted whole-animal model to study, visualise and track the events of wound repair and regeneration in real-time living model systems.

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SnapShot: Connexins and Disease

Abstract: The connexin family of membrane proteins enable gap junction formation and homeostasis, supporting communication between adjacent cells. This SnapShot highlights mutations in different connexins associated with human pathologies and how they affect gap junction function.

Cited by 46 publications

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Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel

Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Connexin Communication Compartments and Wound Repair in Epithelial Tissue

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