Anoxia-mediated calcium release through the mitochondrial permeability transition pore silences NMDA receptor currents in turtle neurons

Hawrysh, Peter John; Buck, Leslie T.

doi:10.1242/jeb.092650

Cited by 38 publications

(42 citation statements)

References 52 publications

(65 reference statements)

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“…The Journal of Experimental Biology (2014) Anoxia-mediated activation of mK ATP channels leads to mitochondrial Ca 2+ release and prevents excessive NMDA receptor currents (Hawrysh and Buck, 2013;Pamenter et al, 2008a;Zivkovic and Buck, 2010). However, this occurs at the same time as decreasing [ROS] i , which we found to increase NMDA receptor currents.…”

Section: Research Articlementioning

confidence: 59%

“…We have proposed that it is the result of mK ATP activation and subsequent formation of lowconductance mitochondrial permeability transition pores (mPTPs) (Pamenter et al, 2008a;Zivkovic and Buck, 2010;Hawrysh and Buck, 2013). mK ATP channels remain closed under normoxic conditions when ATP levels are high and are activated during anoxia as mitochondrial ATP production decreases.…”

Section: Research Articlementioning

confidence: 99%

“…Opening of the channel permits an influx of K + into the mitochondria that triggers mPTP formation and Ca 2+ release (Murchison and Griffith, 2000). In the western painted turtle, addition of the mPTP activator atractyloside decreases NMDA receptor currents and increases [Ca 2+ ] i to levels comparable to those induced by anoxia, and the addition of the Ca 2+ chelator BAPTA blocks the decrease in NMDA receptor currents (Hawrysh and Buck, 2013). The mechanism through which an increase in [Ca 2+ ] i brings about a decrease in NMDA and AMPA receptor currents has previously been attributed to increases in the activity of the Ca 2+ -binding messenger protein calmodulin (Ca 2+ /calmodulin) and subsequent activation of the Ca 2+ /calmodulindependent phosphatase PP2B (calcineurin) (Shin et al, 2005).…”

Section: Research Articlementioning

confidence: 99%

“…To assess treatment effects on ROS generation, the fluorescence at treatment steady state was compared with a linear regression line fit to the 10 min normoxic portion of the trace. Data are presented as percent change expressed relative to that fitted normoxic regression line (Crowe et al, 1995 (Hawrysh and Buck, 2013). Cortical sheets were incubated in aCSF containing 5 μmol l −1…”

Section: Cm-dcf Fluorescence Measurements For [Ros] Imentioning

confidence: 99%

“…The anoxic downregulation of NMDA and AMPA receptor currents is the result of a mitochondrialbased Ca 2+ signalling cascade that is initiated by the activation of the mitochondrial ATP-sensitive potassium (mK ATP ) channel. Although the mechanism through which anoxia activates mK ATP channels has yet to be established, its activation initiates a decrease in mitochondrial membrane potential (Ψ m ) and triggers subsequent mitochondrial Ca 2+ release (Hawrysh and Buck, 2013;Pamenter et al, 2008a;Zivkovic and Buck, 2010). The effect of changing [ROS] on NMDA/AMPA receptor activity or [Ca 2+ ] i in turtle cortical pyramidal neurons has not been explored, although studies in other vertebrate species demonstrate that NMDA receptor activity is significantly increased by a decrease in ROS levels (Aizenman et al, 1989;Bodhinathan et al, 2010;Choi and Lipton, 2000).…”

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confidence: 99%

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Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Dukoff

Hogg

Hawrysh

et al. 2014

Journal of Experimental Biology

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Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-Daspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca 2+ concentrations ([Ca 2+ ] i ) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or Nacetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca 2+ ] i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca 2+ release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATPsensitive potassium (mK ATP ) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. INTRODUCTIONAerobic organisms use diatomic oxygen (O 2 ) as the terminal electron acceptor of the mitochondrial electron transport chain. As a result of inconsistencies in electron flux, a portion of all oxygen consumed (~3%) is left partially reduced as the superoxide anion (Chen et al., 2003;Liu et al., 2002). This highly reactive molecule reacts rapidly with water, leading to the formation of other reactive oxygen species (ROS), the most prevalent and stable of which is (Starkov, 2008). Recently, changes in ROS levels have been identified to play roles in feedback systems and cellular signalling processes through reversible oxidation of critical cysteine residues on target proteins that can alter protein conformation and levels of activity (Cross and Templeton, 2006;D'Autréaux and Toledano, 2007;Rhee et al., 2003). In the absence of O 2 (anoxia) ROS production ceases and it is not known what effects this may have on cellular metabolism or health. For the most part it is a non-issue as most vertebrate species are unable to survive under anoxic conditions and are deleteriously affected by more than a few minutes of O 2 deprivation. Damage is most rapidly incurred within the central nervous system, where the loss of oxidative phosphorylation reduces ATP production to levels that cannot sustain the high energetic demands of neural tissue. Na + /K + -ATPase activity decreases and membrane ion gradients are lost, leading to membrane potential depolarization, increased action potenti...

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Section: Research Articlementioning

confidence: 59%

Section: Research Articlementioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Section: Cm-dcf Fluorescence Measurements For [Ros] Imentioning

confidence: 99%

mentioning

confidence: 99%

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Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Dukoff

Hogg

Hawrysh

et al. 2014

Journal of Experimental Biology

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Mitochondrial matrix pH acidifies during anoxia and is maintained by the F₁F_o‐ATPase in anoxia‐tolerant painted turtle cortical neurons

Hawrysh

Buck

2019

FEBS Open Bio

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The western painted turtle (Chrysemys picta bellii) can survive extended periods of anoxia via a series of mechanisms that serve to reduce its energetic needs. Central to these mechanisms is the response of mitochondria, which depolarize in response to anoxia in turtle pyramidal neurons due to an influx of K+. It is currently unknown how mitochondrial matrix pH is affected by this response and we hypothesized that matrix pH acidifies during anoxia due to increased K+/H+ exchanger activity. Inhibition of K+/H+ exchange via quinine led to a collapse of mitochondrial membrane potential (Ψm) during oxygenated conditions in turtle cortical neurons, as indicated by rhodamine‐123 fluorescence, and this occurred twice as quickly during anoxia which indicates an elevation in K+ conductance. Mitochondrial matrix pH acidified during anoxia, as indicated by SNARF‐1 fluorescence imaged via confocal microscopy, and further acidification occurred during anoxia when the F1Fo‐ATPase was inhibited with oligomycin‐A, indicating that ΔpH collapse is prevented during anoxic conditions. Collectively, these results indicate that the mitochondrial proton electrochemical gradient is actively preserved during anoxia to prevent a collapse of Ψm and ΔpH.

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The δ-Opioid Receptor and Stabilization of Brain Ionic Homeostasis in Hypoxia/Ischemia

Chao¹,

Xia²

2015

Neural Functions of the Delta-Opioid Receptor

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Anoxia-mediated calcium release through the mitochondrial permeability transition pore silences NMDA receptor currents in turtle neurons

Cited by 38 publications

References 52 publications

Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Mitochondrial matrix pH acidifies during anoxia and is maintained by the F₁F_o‐ATPase in anoxia‐tolerant painted turtle cortical neurons

The δ-Opioid Receptor and Stabilization of Brain Ionic Homeostasis in Hypoxia/Ischemia

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Anoxia-mediated calcium release through the mitochondrial permeability transition pore silences NMDA receptor currents in turtle neurons

Cited by 38 publications

References 52 publications

Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Scavenging ROS dramatically increases NMDA receptor whole cell currents in painted turtle cortical neurons

Mitochondrial matrix pH acidifies during anoxia and is maintained by the F1Fo‐ATPase in anoxia‐tolerant painted turtle cortical neurons

The δ-Opioid Receptor and Stabilization of Brain Ionic Homeostasis in Hypoxia/Ischemia

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Mitochondrial matrix pH acidifies during anoxia and is maintained by the F₁F_o‐ATPase in anoxia‐tolerant painted turtle cortical neurons