Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration

Álvarez, Álvaro; Lagos-Cabré, Raúl; Kong, Milene; Cárdenas, Areli; Burgos‐Bravo, Francesca; Schneider, Pascal; Quest, Andrew F. G.; Leyton, Lisette

doi:10.1016/j.bbamcr.2016.05.018

Cited by 45 publications

(121 citation statements)

References 78 publications

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“…ATP release and P2X 7 receptor activation have also been shown to be initiated in response to ligand-activated α V β 3 integrin and syndecan-4 engagement leading to increased formation of focal adhesions and an enhanced rate of migration in astrocytes [8]. The mechanism of ATP release involved activation of PI3K, PLCγ and IP 3 receptors following integrin activation.…”

Section: Ion Channels and Cell Motilitymentioning

confidence: 99%

CFTR Involvement in Cell Migration and Epithelial Restitution

O’Grady¹

2017

Progress in Understanding Cystic Fibrosis

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Over the past decade, research has shown that cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in epithelial cell migration and wound healing. Experiments with airway epithelium, ovarian epithelial cells, placental epithelium and epidermal keratinocytes demonstrated that CFTR function is necessary to achieve maximum migration rates during restitution and in certain cancer cells, CFTR activity contributes to tumor cell invasion. Multiple mechanisms appear to underlie the motility-promoting actions of CFTR, and although many details remain to be established, our present understanding indicates that processes such as electrotaxis (galvanotaxis), integrin-mediated cell adhesion and lamellipodia protrusion are dependent on normal CFTR function. In this chapter, the role of CFTR in epithelial cell migration and its implications in cystic fibrosis (CF) will be reviewed with emphasis on the underlying mechanisms that may explain observations made in various epithelial tissues, particularly in airways. Ultimately, a better understanding of CFTR involvement in epithelial repair may lead to new therapeutic approaches to improve barrier function and reduce airway infection and inflammation associated with CF.

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Section: Ion Channels and Cell Motilitymentioning

confidence: 99%

CFTR Involvement in Cell Migration and Epithelial Restitution

O’Grady¹

2017

Progress in Understanding Cystic Fibrosis

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“…Nevertheless, astrocytes first need to become “reactive” and increase the levels of membrane receptors and channels in order to respond to Thy-1 [4,5]. Reactive astrocytes are characterized by morphological changes (i.e., increase in size and arborization of processes) and substantial changes in the protein expression profile as a response to pathological conditions in the CNS, such as neurodegenerative diseases, stroke or traumatic injuries [2,3,4,5]. The “reactive” phenotype can also be replicated in vitro by the addition of proinflammatory cytokines, such as tumor necrosis factor TNF or IL-1β [4], which are released by reactive astrocytes and microglia in an injured brain [6].…”

Section: Introductionmentioning

confidence: 99%

“…These reactive astrocytes increase the expression of the two reported Thy-1 receptors, αvβ3 integrin and Syndecan-4, among other proteins [4]. When bound to Thy-1, the engaged receptors trigger an intracellular signaling cascade involving FAK, PLCγ, inositol 1,4,5-trisphosphate receptor (IP 3 R) activation, Ca 2+ release from the endoplasmic reticulum, connexin (Cx)- and pannexin (Px)-hemichannel opening, ATP release, and finally P2X7 receptor (P2X7R) activation, which further increases intracellular Ca 2+ concentrations ([Ca 2+ ]i) [4,5,6,7,8]. In this complex sequence, connexin 43 (Cx43) channels play an important role not only to allow the release of ATP to the extracellular medium, but also to communicate with the surrounding cells by gap junctions [5,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…After inducing astrocyte reactivity in vitro, Cx43 is overexpressed and pharmacological inhibition precludes astrocyte migration [4,5,11]. In normal conditions, Cx43 is mostly localized in intracellular vesicles.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, pro-inflammatory conditions induced by cytokines or neurodegenerative diseases also increase Cx43 protein levels and hemichannel activity [4,14], suggesting that under these conditions, gap junction activity is diminished, while hemichannels appear more active. Furthermore, the role of Cx43 in hemichannel formation and astrocyte migration appears especially relevant in brain injuries, since specific hemichannel inhibitory peptides abolish astrocyte migration [5], an important process required for glial scar formation [15]. …”

Section: Introductionmentioning

confidence: 99%

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Intracellular Ca2+ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration

Lagos-Cabré

Brenet

Díaz

et al. 2018

IJMS

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Under pro-inflammatory conditions, astrocytes become reactive and acquire a migratory phenotype. Our results show that hemichannels formed by connexin 43 (Cx43) play an important role in Thy-1-induced astrocyte migration. The neuronal protein Thy-1 binds to αvβ3 integrin in astrocytes, thereby leading to intricate signaling pathways that include calcium (Ca2+) release from intracellular stores, opening of Cx43 hemichannels, release of ATP, activation of P2X7 receptor, and Ca2+ influx. However, because these Thy-1 effects occur exclusively in reactive astrocytes, we wondered whether by elevating calcium levels and promoting hemichannel opening we could prompt non-reactive astrocytes to respond to Thy-1. Cx43 immunoreactivity increased at juxta-membrane sites, where hemichannels (not gap junctions) participate in astrocyte polarization and migration stimulated by Thy-1. Also, intracellular Ca2+ increase, due to ionomycin treatment, induced hemichannel opening, but activated astrocyte migration only partially, and this limitation was overcome by pre-treatment with tumor necrosis factor (TNF) and Thy-1. Finally, αvβ3 integrin formed membrane clusters after TNF stimulation or overexpression of β3 integrin. We suggest that these microclusters are required for cells to respond to Thy-1 stimulation. Therefore, the large increase in intracellular Ca2+ and hemichannel opening induced by ionomycin are required, but not sufficient, to permit Thy-1-induced astrocyte migration. Thus, we suggest that proinflammatory stimuli prompt astrocytes to respond to migratory signals of neuronal cells.

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Investigation of cytotoxic effect of the bufanolide steroid compound cinobufagin and its related underlying mechanism in brain cell models

Hsu

Lin

Liang

2021

J Biochem & Molecular Tox

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Cinobufagin, a bufadienolide of toad venom of Bufo bufo gargarizans, is used as a cardiotonic, central nervous system (CNS) respiratory agent, as well as an analgesic and anesthetic. However, several research showed that bufadienolide has a few side effects on the CNS, such as breathlessness or coma. Although cinobufagin was shown to display pharmacological effects in various models, the toxic effect of cinobufagin is elusive in brain cell models. The aim of this study was to explore whether cinobufagin affected viability, Ca 2+ homeostasis, and reactive oxygen species (ROS) production in Gibco ® Human Astrocyte (GHA) and HCN-2 neuronal cell line. In GHA cells but not in HCN-2 cells, cinobufagin (20-60 μM) induced [Ca 2+ ] i rises. In terms of cell viability, chelation of cytosolic Ca 2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid reduced cinobufagin-induced cytotoxicity in GHA cells. In GHA cells, cinobufagin-induced Ca 2+ entry was inhibited by 2-aminoethoxydiphenyl borate or SKF96365. In a Ca 2+ -free medium, treatment with thapsigargin or U73122 abolished cinobufagin-evoked [Ca 2+ ] i rises. Furthermore, treatment with N-acetylcysteine reversed ROS production and cytotoxicity in cinobufagin-treated GHA cells. Together, in GHA cells but not in HCN-2 cells cinobufagin caused cytotoxicity that was linked to preceding [Ca 2+ ] i rises by Ca 2+ influx via store-operated Ca 2+ entry and phospholipase C-dependent Ca 2+ release from the endoplasmic reticulum. Moreover, cinobufagin induced ROS-associated cytotoxicity.brain cell models Ca 2+ homeostasis, cinobufagin, cytotoxicity, ROS | INTRODUCTIONChan Su, a traditional herbal medicine, is prepared from the skin glands of toad venom Bufo bufo gargarizans Cantor. [1,2] The major active components in Chan Su are bufadienolides, such as bufalin, cinobufagin, and resibufogenin. Bufadienolides, a group of steroid hormones, were shown to block the adenosine triphosphatase sodium-potassium pump, Na + /K + -ATPase. [3][4][5] Bufadienolides displayed many pharmacological effects through Na + /K + -ATPase, such as reduction of inflammation, [6] enhancement of cardiac contractility, [7] and inhibition of tumor. [8] Furthermore, cinobufagin was shown to have pharmacological applications in cancer treatment and analgesic properties. [9,10] The chemical structure of bufadienolides has similarities to digoxin, which is used to treat various heart conditions. [4,11,12] However, it has been shown that bufadienolides exhibit cardiotoxic effects by competing with K + ions for the same binding site on the Na + /K + -ATPase pump. [4,11,12] © 2021 Wiley Periodicals LLC Cinobufagin was reported to induce cytotoxicity in various cell models. It has been shown that cinobufagin induced apoptosis in MCF-7 human breast cancer cells [13] and 143B human osteosarcoma cells, [14] caused autophagy in U2OS human osteosarcoma cells, [15] evoked cell cycle arrest in MDA-MB-231 human breast cancer cells, [16] and exerted antiproliferation in U266 human multiple myeloma cells. [17] In Ca ...

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Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration

Cited by 45 publications

References 78 publications

CFTR Involvement in Cell Migration and Epithelial Restitution

CFTR Involvement in Cell Migration and Epithelial Restitution

Intracellular Ca2+ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration

Investigation of cytotoxic effect of the bufanolide steroid compound cinobufagin and its related underlying mechanism in brain cell models

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