Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Haskew-Layton, Renée E.; Mongin, Alexander A.; Kimelberg, Harold K.

doi:10.1074/jbc.m409803200

Cited by 43 publications

(43 citation statements)

References 80 publications

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“…During a number of pathological states such as ischemia or trauma, astrocytic swelling is an early event and leads to opening of VRACs (Kimelberg, 2000;Kimelberg, 2005). The number of different VRACs that are present, which ones open under particular types and degrees of swelling, and which compounds permeate these are all topics of current research in this area (Mongin and Kimelberg, 2004;Haskew-Layton et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Zhang

Feustel

et al. 2008

Experimental Neurology

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Previous studies have indicated that volume regulated anion channels (VRACs) may be involved in the pathology of the ischemic brain cortical penumbra due to activation of VRAC-mediated excitatory amino-acid (EAA) release. To assess this we had studied neuroprotection and EAA release inhibition by a potent VRAC inhibitor, tamoxifen. However, tamoxifen inhibits several other neurodamaging processes. In the present study we use an ethacrynic acid derivative, 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), that has recently been shown to be a specific antagonist of volume regulated anion channels (VRAC), to measure the extent of neuroprotection provided and thus to better assess the role of VRAC-mediated release of excitatory amino acids in an intraluminal suture, reversible middle cerebral artery occlusion (rMCAO) model in adult rats. Rats given DCPIB intracisternally had significantly better neurobehavioral scores after 24 hours and showed significantly reduced infarct volumes. Mean infarct volumes were 208.0 (SD = 38.3) mm 3 for the vehicle groups, compared with 68.5 (SD = 22.7) mm 3 for intracisternally DCPIBtreated groups (p=0.02, Mann-Whitney test), a reduction of around 75%. However, a 500-fold higher dose of DCPIB given intravenously did not reduce infarct volume or improve behavior. The microdialysis study demonstrated statistically significant reduced brain extracellular fluid glutamate when DCPIB was present in the probe. Thus DCPIB, a specific inhibitor of VRACs, given i.c. provides strong neuroprotection in brain ischemia, but it appears to not cross the blood brain barrier as it is not effective when given i.v. These experiments support the hypothesis that EAA released via VRACs contributes to later ischemic-induced damage.

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Section: Discussionmentioning

confidence: 99%

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Zhang

Feustel

et al. 2008

Experimental Neurology

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113

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“…Several recent in vitro studies have found that a number ob substances, which are produced ore released in ischemia, such as reactive oxygen species H 2 O 2 , reactive nitrogen species peroxynitrite, thrombin, and ATP, all drastically increase swelling-activated glutamate release from moderately swollen astrocytes [69][70][71][72].…”

Section: Volume-regulated Anion Channels and The Reversed Mode Of Glumentioning

confidence: 99%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

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“…Although the identity of the swelling-activated D-[ 3 H]aspartate release pathway has not been addressed in this study, the involvement of VRAC in astrocytic excitatory amino acid release in the absence or presence of ATP was previously verified by using several pharmacological inhibitors including the selective VRAC blocker DCPIB (Mongin and Kimelberg 2002;Haskew-Layton et al 2005;Abdullaev et al 2006). DCPIB potently and selectively blocks the VRAC activity measured electrophysiologically or as swellingactivated release of D-[ 3 H]aspartate release (Decher et al 2001;Abdullaev et al 2006).…”

Section: Discussionmentioning

confidence: 96%

“…We have previously found that although the PKC inhibitors chelerythrine and bisindolylmaleimide potently suppress the effect of ATP on VRAC activity, two other selective PKC blockers, Go6983 and Ro-32-0432, are marginally effective Haskew-Layton et al 2005). Our present work unequivocally demonstrates that Ca 2+ -dependent conventional PKCs are major contributors to the P2Y receptor-dependent VRAC regulation in astrocytes.…”

Section: Conventional Pkc Isoforms Are Major Contributors To Vrac Regmentioning

confidence: 99%

“…In our previous work, we have found that although some of the PKC inhibitors (such as chelerythrine and bisindolylmaleimide) potently blocked ATP-dependent VRAC activation, others (such as Go6983 and Ro-32-0432) showed little efficacy Haskew-Layton et al 2005). In other cell types, PKC has been reported to play either major or minor role in the GPCR-dependent regulation of organic osmolyte release via VRAC (Loveday et al 2003;Falktoft and Lambert 2004;Cheema et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Two conventional protein kinase C isoforms, α and βI, are involved in the ATP‐induced activation of volume‐regulated anion channel and glutamate release in cultured astrocytes

Rudkouskaya

Chernoguz

Haskew-Layton

et al. 2008

Journal of Neurochemistry

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Volume-regulated anion channels (VRACs) are activated by cell swelling and are permeable to inorganic and small organic anions, including the excitatory amino acids glutamate and aspartate. In astrocytes, ATP potently enhances VRAC activity and glutamate release via a P2Y receptordependent mechanism. Our previous pharmacological study identified protein kinase C (PKC) as a major signaling enzyme in VRAC regulation by ATP. However, conflicting results obtained with potent PKC blockers prompted us to re-evaluate PKC involvement in regulation of astrocytic VRAC using siRNA and pharmacological inhibitors that selectively target individual PKC isoforms. In primary rat astrocyte cultures, application of hypoosmotic medium (30% reduction in osmolarity) and 20 M ATP synergistically increased the release of excitatory amino acids, measured with non-metabolized analogue of L-glutamate, D-[ 3 H]aspartate. Both Go6976, the selective inhibitor of Ca 2+ -sensitive PKC , I/II, and , and MP-20-28, a cell permeable pseudosubstrate inhibitory peptide of PKC and I/II, reduced the effects of ATP on D-[ 3 H]aspartate release by ~45-55%. Similar results were obtained with a mixture of siRNAs targeting rat PKC and I. Surprisingly, downregulation of individual and I PKC isozymes by siRNA was completely ineffective. These data suggest that ATP regulates VRAC activity and volume-sensitive excitatory amino acid release via cooperative activation of PKC and I.

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Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Abstract: Excessive excitatory amino acid (EAA) release in cerebral ischemia is a major mechanism responsible for neuronal damage and death. A substantial fraction of ischemic EAA release occurs via volume-regulated anion channels (VRACs

Cited by 43 publications

References 80 publications

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Two conventional protein kinase C isoforms, α and βI, are involved in the ATP‐induced activation of volume‐regulated anion channel and glutamate release in cultured astrocytes

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