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Cited by 103Neuroinflammation and Neurodegeneration MechanismsRedox biology and oxidative stressIon Transport and Channel Regulation

Activation of microglia with zymosan promotes excitatory amino acid release via volume‐regulated anion channels: the role of NADPH oxidases

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Harrigan, Timothy J., Abdullaev, Iskandar F., Jourd’heuil, David, Mongin, Alexander A.·2008·Journal of Neurochemistry
DOI 10.1111/j.1471-4159.2008.05553.xPMC PMC2574595
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Abstract

Microglia are the resident immune cells of the CNS, which are important for preserving neural tissue functions, but may also contribute to neurodegeneration. Activation of these cells in infection, inflammation, or trauma leads to the release of various toxic molecules, including reactive oxygen species (ROS) and the excitatory amino acid glutamate. In this study, we used an electrophysiologic approach and a d‐[3H]aspartate (glutamate) release assay to explore the ROS‐dependent regulation of glutamate‐permeable volume‐regulated anion channels (VRACs). Exposure of rat microglia to hypo‐osmotic media stimulated Cl− currents and d‐[3 H]aspartate release, both of which were inhibited by the selective VRAC blocker, DCPIB. Exogenously applied H 2 O 2 potently increased swelling‐activated glutamate release. Stimulation of microglia with zymosan triggered production of endogenous ROS and strongly enhanced glutamate release via VRAC in swollen cells. The effects of zymosan were attenuated by the ROS scavenger, MnTMPyP, and by two inhibitors of NADPH oxidase (NOX), diphenyliodonium and thioridazine. However, zymosan‐stimulated glutamate release was insensitive to other NOX blockers, apocynin and HEBSF. This pharmacologic profile pointed to the potential involvement of apocynin‐insensitive NOX4. Using RT‐PCR we confirmed that NOX4 is expressed in rat microglial cells along with NOX1 and NOX2. To check for potential involvement of phagocytic NOX2, we stimulated this isoform using protein kinase C (PKC) activator, phorbol 12‐myristate 13‐acetate or inhibited it with the broad spectrum PKC blocker, Gö6983. Both agents potently modulated endogenous ROS production by NOX2 but not VRAC activity. Taken together, these data suggest that the anion channel VRAC may contribute to microglial glutamate release and that its activity is regulated by endogenous ROS originating from NOX4.

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Authors
Harrigan, T. J., Abdullaev, I. F., Jourd’heuil, D., & Mongin, A. A.
Affiliations
Albany Medical College (US)
Corresponding author
Mongin, Alexander A.
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2008-09
Volume
106
Issue
6
Pages
2449-2462
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/j.1471-4159.2008.05553.x
PMC
PMC2574595
OpenAlex
W2000397596
Cited by
103
References
7
Citations by year
2025: 1 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 13 · 2016: 9 · 2015: 4 · 2014: 10 · 2013: 7 · 2012: 13
FWCI
3.78
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Drug Abuse (T32DA007307)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
microglial activation, zymosan, glutamate release, volume-regulated anion channel, NADPH oxidase, NOX4, reactive oxygen species, cell swelling, chloride currents, neuroinflammation, excitatory amino acids, NOX2, protein kinase C
MeSH terms
NADPH Oxidase 4, Animals, Animals, Newborn, Aspartic Acid, Cells, Cultured, Encephalitis, Enzyme Inhibitors, Isoenzymes, Protein Kinase C, Zymosan, Oxidants, Rats, Sprague-Dawley, Reactive Oxygen Species, Microglia, Oxidative Stress, Glutamic Acid, Excitatory Amino Acids, NADPH Oxidases, Voltage-Dependent Anion Channels, Rats

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