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Open AccessArticle

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

1
Cellular Communication Laboratory, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 838-0453, Chile
2
Advanced Center for Chronic Diseases (ACCDiS), Center for Studies on Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 838-0453, Chile
3
Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
4
Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O’Higgins, Santiago 837-0993, Chile
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(8), 2179; https://doi.org/10.3390/ijms19082179
Received: 7 June 2018 / Revised: 5 July 2018 / Accepted: 7 July 2018 / Published: 26 July 2018
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. View Full-Text
Keywords: connexin 43 hemichannels; gap junctions; cell polarization; cell migration; inflammation; reactive astrocytes; neuronal signals connexin 43 hemichannels; gap junctions; cell polarization; cell migration; inflammation; reactive astrocytes; neuronal signals
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Lagos-Cabré, R.; Brenet, M.; Díaz, J.; Pérez, R.D.; Pérez, L.A.; Herrera-Molina, R.; Quest, A.F.G.; Leyton, L. Intracellular Ca2+ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration. Int. J. Mol. Sci. 2018, 19, 2179.

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