Oncotarget

Research Papers:

Coordinate effects of P2X7 and extracellular acidification in microglial cells

Ponarulselvam Sekar, Duen-Yi Huang, Shwu-Fen Chang, Wan-Wan Lin _

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Oncotarget. 2018; 9:12718-12731. https://doi.org/10.18632/oncotarget.24331

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Abstract

Ponarulselvam Sekar1, Duen-Yi Huang2, Shwu-Fen Chang1 and Wan-Wan Lin1,2

1Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

2Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

Correspondence to:

Wan-Wan Lin, email: wwllaura1119@ntu.edu.tw

Keywords: P2X7; ATP; acidification; mitochondrial respiration; mitochondrial fission

Received: April 20, 2017     Accepted: January 24, 2018     Published: January 29, 2018

ABSTRACT

Extracellular adenosine 5′-triphosphate (ATP) is a damage-associated molecular pattern and contributes to inflammation associated diseases including cancer. Extracellular acidosis is a novel danger signal in the inflammatory sites, where it can modulate inflammation, immunity and tumor growth. Extracellular acidification was shown to inhibit P2X7-mediated channel currents, while it remains unknown how acidification and P2X7 together affect cellular responses. Here, we treated BV-2 microglial cells with ATP in a short period (<15 min) or a sustained acidified condition. For short acidification we compared the actions of neutralized ATP and acidic ATP in a condition with pH buffering. For sustained acidification, we treated cells with neutralized ATP in acidic medium or acidic ATP in medium without pH buffering. In the short acidified condition, neutralized ATP induced higher responses than acidic ATP to increase intracellular calcium and reactive oxygen species, decrease intracellular potassium and induce cell death. In contrast, these cellular responses and mitochondrial fission caused by neutralized ATP were enhanced by pH 6.0 and pH 4.5 media. P2X7 activation can also rapidly block mitochondrial ATP turnover and respiration capacity, both of which were mimicked by nigericin and enhanced by acidity. Taken together P2X7-mediated ionic fluxes and reactive oxygen species production are attenuated under short acidification, while sustained acidification itself can induce mitochondrial toxicity which deteriorates the mitochondrial function under P2X7 activation.


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