Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration
Author
dc.contributor.author
Álvarez, Álvaro
Author
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Lagos Cabré, Raúl
Author
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Kong, Milene
Author
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Cárdenas, Areli
Author
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Burgos Bravo, Francesca
Author
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Schneider, Pascal
Author
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Quest, Andrew F. G.
Author
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Leyton Campos, Lisette
Admission date
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2016-12-19T20:32:28Z
Available date
dc.date.available
2016-12-19T20:32:28Z
Publication date
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2016
Cita de ítem
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Biochimica et Biophysica Acta 1863 (2016) 2175–2188
es_ES
Identifier
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10.1016/j.bbamcr.2016.05.018
Identifier
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https://repositorio.uchile.cl/handle/2250/141988
Abstract
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Our previous reports indicate that ligand-induced alpha(v)beta(3) integrin and Syndecan-4 engagement increases focal adhesion formation and migration of astrocytes. Additionally, ligated integrins trigger ATP release through unknown mechanisms, activating P2X7 receptors (P2X7R), and the uptake of Ca2+ to promote cell adhesion. However, whether the activation of P2X7R and ATP release are required for astrocyte migration and whether alpha(v)beta(3) integrin and Syndecan-4 receptors communicate with P2X7R via ATP remains unknown. Here, cells were stimulated with Thy-1, a reported alpha(v)beta(3) integrin and Syndecan-4 ligand. Results obtained indicate that ATP was released by Thy-1 upon integrin engagement and required the participation of phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLC-gamma) and inositol trisphosphate (IP3) receptors (IP3R). IP3R activation leads to increased intracellular Ca2+, hemichannel (Connexin-43 and Pannexin-1) opening, and ATP release. Moreover, silencing of the P2X7R or addition of hemichannel blockers precluded Thy-I-induced astrocyte migration. Finally, Thy-1 lacking the integrin-binding site did not stimulate ATP release, whereas Thy-1 mutated in the Syndecan-4-binding domain increased ATP release, albeit to a lesser extent and with delayed kinetics compared to wild-type Thy-1. Thus, hemichannels activated downstream of an alpha(v)beta(3) integrin-PI3K-PLC gamma-IP3R pathway are responsible for Thy-1-induced, hemichannel-mediated and Syndecan-4-modulated ATP release that transactivates P2X7Rs to induce Ca2+ entry. These findings uncover a hitherto unrecognized role for hemichannels in the regulation of astrocyte migration via P2X7R transactivation induced by integrin-mediated ATP release.