Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase II

Bodhinathan, Karthik; Kumar, Ashok; Foster, Thomas C.

doi:10.1523/jneurosci.5485-09.2010

Cited by 142 publications

(175 citation statements)

References 56 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…The increase in NMDA receptor currents resulting from application of reducing agents is generally six to 11 times greater than decreases initiated by oxidizing agents, a ratio comparable to the 5:1 we found for ROS scavenging or H 2 O 2 application in turtle pyramidal neurons (Aizenman et al, 1989;Bodhinathan et al, 2010;Choi and Lipton, 2000). The large increase in receptor currents triggered by ROS scavenging may permit excessive Ca 2+ influx into patched pyramidal cells during NMDA application, explaining why NAC/MPG application often resulted in cell depolarization and death.…”

Section: Research Articlesupporting

confidence: 63%

“…The high sensitivity of NMDA receptors to reducing agents, compared with oxidizers, is thought to be the result of extracellular redox sites being maintained in a predominantly oxidized state because extracellular antioxidants are produced within the cell and are slow to diffuse out (Jones et al, 2000;Ottaviano et al, 2008). This may also explain why the effects of H 2 O 2 were reversed by reperfusion but the effects of MPG and NAC were not, similar to other studies in which the effects of oxidizing but not reducing agents were reversed by washout (Bodhinathan et al, 2010;Köhr et al, 1994). Because cellular ROS production is slow, if extracellular levels are eliminated, it may take some time before baseline concentrations are re-established and scavenging agents are degraded (Ottaviano et al, 2008).…”

Section: Research Articlesupporting

confidence: 59%

“…1989; Bodhinathan et al, 2010;Choi et al, 2001;Choi and Lipton, 2000;Janáky et al, 1993). The increase in NMDA receptor currents resulting from application of reducing agents is generally six to 11 times greater than decreases initiated by oxidizing agents, a ratio comparable to the 5:1 we found for ROS scavenging or H 2 O 2 application in turtle pyramidal neurons (Aizenman et al, 1989;Bodhinathan et al, 2010;Choi and Lipton, 2000).…”

Section: Research Articlesupporting

confidence: 57%

“…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). However, because ROS levels naturally decrease in the anoxic turtle brain, we propose that this will trigger an increase in [Ca 2+ ] i and a decrease in NMDA and AMPA receptor whole-cell currents (Pamenter et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Dukoff

Hogg

Hawrysh

et al. 2014

Journal of Experimental Biology

View full text Add to dashboard Cite

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...

show abstract

Section: Research Articlesupporting

confidence: 63%

Section: Research Articlesupporting

confidence: 59%

Section: Research Articlesupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Dukoff

Hogg

Hawrysh

et al. 2014

Journal of Experimental Biology

View full text Add to dashboard Cite

show abstract

“…The redox state of thiols exerts a profound effect on the physiology of neurons; for instance, it regulates fundamental processes such as synaptic plasticity [45] and controls the conductance of several ion channels involved in neuronal excitability [46,47]. Additionally, thiol oxidation has been involved in zinc finger transcription factor activity [48], transferrin mediated iron accumulation [49], and decrease of TH activity [36].…”

Section: Oxidative Stress and Dopaminergic Damagementioning

confidence: 99%

Redox Sensitivity of Tyrosine Hydroxylase Activity and Expression in Dopaminergic Dysfunction

Giovanni

Pessia²,

Maio³

2012

CNSNDDT

View full text Add to dashboard Cite

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson's disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression.The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.

show abstract

Simultaneous intrathecal injection of muscimol and endomorphin‐1 alleviates neuropathic pain in rat model of spinal cord injury

et al. 2020

View full text Add to dashboard Cite

Introduction Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin‐1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α2 subunits of GABA receptors in the spinal cord has also been investigated. Methods Spinal cord at level of T6–T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin‐1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples. Results Isobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin‐1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord. Conclusion Simultaneous administration of muscimol and endomorphine‐1 could be a new candidate for alleviation of pain resulting from spinal cord injury.

show abstract

Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca²⁺/Calmodulin-Dependent Protein Kinase II

Cited by 142 publications

References 56 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

Redox Sensitivity of Tyrosine Hydroxylase Activity and Expression in Dopaminergic Dysfunction

Simultaneous intrathecal injection of muscimol and endomorphin‐1 alleviates neuropathic pain in rat model of spinal cord injury

Contact Info

Product

Resources

About

Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca2+/Calmodulin-Dependent Protein Kinase II

Cited by 142 publications

References 56 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

Redox Sensitivity of Tyrosine Hydroxylase Activity and Expression in Dopaminergic Dysfunction

Simultaneous intrathecal injection of muscimol and endomorphin‐1 alleviates neuropathic pain in rat model of spinal cord injury

Contact Info

Product

Resources

About

Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca²⁺/Calmodulin-Dependent Protein Kinase II