Evidence that the Early Loss of Membrane Protein Kinase C Is a Necessary Step in the Excitatory Amino Acid‐Induced Death of Primary Cortical Neurons

Durkin, Jon P.; Tremblay, Roger; Chakravarthy, Balu; Mealing, Geoff; Morley, Paul; Small, Daniel L.; Song, Dekun

doi:10.1046/j.1471-4159.1997.68041400.x

Cited by 83 publications

(58 citation statements)

References 36 publications

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“…PKC is a central protein in neuronal metabolism, function, and survival (Dekker and Parker, 1994), and changes in PKC activity have been hypothesized to play either a protective or a detrimental role in the cell death, including ischemic damage (Hara et al, 1990;Busto et al, 1994;Durkin et al, 1997). However, we could not detect any significant effects of various PKC inhibitors treated alone on hypoxia-reperfusioninduced necrosis in additional experiments (Fig.…”

Section: Pkc-␥ Activation In Insulin Signaling Prevents Necrosis 1031mentioning

confidence: 74%

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Hamabe

Fujita²,

Ueda³

2005

J Pharmacol Exp Ther

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Ischemic stress causes neuronal death and functional impairment. Evidence has suggested that cells in the ischemic core first lose viability due to the decline in blood flow and cellular energy metabolism and then die by necrosis. Although inhibition of necrosis could be a potent therapeutic target for brain ischemia, known neurotrophic factors are ineffective for neuronal necrosis. We previously reported that insulin, but not brainderived neurotrophic factor or insulin like-growth factor-1, inhibited neuronal necrosis under serum-free starvation stress. Although insulin receptors are abundant in the central nervous system as well as in peripheral tissues, neurons are not dependent upon insulin for their glucose supply, indicating that insulin receptors have other roles in the central nervous system. In the present study, by using hypoxia-reperfusion stress, we showed that cortical neurons rapidly died by necrosis as evaluated by propidium iodide staining and transmission electron microscopic analysis. As expected, insulin treatment significantly inhibited neuronal necrosis, although this effect was blocked by pretreatment with an antisense oligonucleotide for the insulin receptor. Furthermore, an inhibitor of protein kinase C (PKC) eliminated the insulin-induced antinecrotic effect. The addition of insulin induced significant translocation of only the PKC-␥ isoform, whereas antisense oligonucleotide treatment for this isoform abolished the insulin-induced inhibition of necrosis. Together, these results suggest that insulin mediates inhibition of neuronal necrosis through a novel mechanism involving PKC-␥ activation.

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Section: Pkc-␥ Activation In Insulin Signaling Prevents Necrosis 1031mentioning

confidence: 74%

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Hamabe

Fujita²,

Ueda³

2005

J Pharmacol Exp Ther

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“…Its loss of function, especially upon OS exposure, correlates with the severity of the damage (26,37). Therefore, we investigated the possible involvement of PKC in the neuroprotective activity of EGCG against 6-OHDA-induced neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Involvement of Protein Kinase C Activation and Cell Survival/ Cell Cycle Genes in Green Tea Polyphenol (−)-Epigallocatechin 3-Gallate Neuroprotective Action

Levites¹,

Amit²,

Youdim³

et al. 2002

Journal of Biological Chemistry

393

324

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Studies from our laboratory have demonstrated that the major green tea polyphenol, (؊)-epigallocatechin 3-gallate (EGCG), exerts potent neuroprotective actions in the mice model of Parkinson's disease. These studies were extended to neuronal cell culture employing the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA). Pretreatment with EGCG (0.1-10 M) attenuated human neuroblastoma (NB) SH-SY5Y cell death, induced by a 24-h exposure to 6-OHDA (50 M). Potential cell signaling candidates involved in this neuroprotective effect were further examined. EGCG restored the reduced protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) activities caused by 6-OHDA toxicity. However, the neuroprotective effect of EGCG on cell survival was abolished by pretreatment with PKC inhibitor GF 109203X (1 M). Because EGCG increased phosphorylated PKC, we suggest that PKC isoenzymes are involved in the neuroprotective action of EGCG against 6-OHDA. In addition, gene expression analysis revealed that EGCG prevented both the 6-OHDA-induced expression of several mRNAs, such as Bax, Bad, and Mdm2, and the decrease in Bcl-2, Bcl-w, and Bcl-x L . These results suggest that the neuroprotective mechanism of EGCG against oxidative stressinduced cell death includes stimulation of PKC and modulation of cell survival/cell cycle genes.

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“…It is more likely that excitotoxic stimulation would trigger second messenger cascades, leading to post-translational modifications of existing membrane proteins or activation of a dormant channel to activate I EIC . Indeed, NMDA-dependent changes in protein phosphorylation Durkin et al, 1997), protease activity such as the calpains (Minger et al, 1998;Simpkins et al, 2003), and numerous other second messenger effects have been reported during glutamate excitotoxicity. Such alterations in key proteins or enzyme activities could result in the activation of the I EIC -Ca 2ϩ -permeable channel.…”

Section: Discussionmentioning

confidence: 99%

Activation of a Novel Injury-Induced Calcium-Permeable Channel That Plays a Key Role in Causing Extended Neuronal Depolarization and Initiating Neuronal Death in Excitotoxic Neuronal Injury

Deshpande

Limbrick²,

Sombati³

et al. 2007

J Pharmacol Exp Ther

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Protracted elevation in intracellular calcium caused by the activation of the N-methyl-D-aspartate receptor is the main cause of glutamate excitotoxic injury in stroke. However, upon excitotoxic injury, despite the presence of calcium entry antagonists, calcium unexpectedly continues to enter the neuron, causing extended neuronal depolarization and culminating in neuronal death. This phenomenon is known as the calcium paradox of neuronal death in stroke, and it represents a major problem in developing effective therapies for the treatment of stroke. To investigate this calcium paradox and to determine the source of this unexpected calcium entry after neuronal injury, we evaluated whether glutamate excitotoxicity activates an injury-induced calcium-permeable channel responsible for conducting a calcium current that underlies neuronal death. We used a combination of whole-cell and single-channel patchclamp recordings, fluorescent calcium imaging, and neuronal cell death assays in a well characterized primary hippocampal neuronal culture model of glutamate excitotoxicity/stroke. Here, we report activation of a novel calcium-permeable channel upon excitotoxic glutamate injury that carries calcium current even in the presence of calcium entry inhibitors. Blocking this injury-induced calcium-permeable channel for a significant time period after the initial injury is still effective in preventing calcium entry, extended neuronal depolarization, and delayed neuronal death, thereby accounting for the calcium paradox. This injury-induced calcium-permeable channel represents a major source for the initial calcium entry following stroke, and it offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.Stroke is a leading cause of disability and death, yet its successful treatment is limited (Bonita et al., 2004). Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system, and it is required for neural development, synaptogenesis, and alterations in synaptic plasticity (Dingledine et al., 1999). In excessive quantities, glutamate is thought to cause the neuronal damage observed following stroke, epilepsy, and traumatic brain injury (Siesjö and Bengtsson, 1989;Delorenzo et al., 2005). Protracted elevation in intracellular calcium [Ca 2ϩ ] i caused by the activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is the main cause of excitotoxic injury in stroke (Choi, 1995;Lipton, 1999). Excitotoxic glutamate exposure causes two major, long-lasting changes in neuronal physiology. Our laboratory and others have demonstrated that glutamate exposure results in a prolonged dis-

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Evidence that the Early Loss of Membrane Protein Kinase C Is a Necessary Step in the Excitatory Amino Acid‐Induced Death of Primary Cortical Neurons

Cited by 83 publications

References 36 publications

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Involvement of Protein Kinase C Activation and Cell Survival/ Cell Cycle Genes in Green Tea Polyphenol (−)-Epigallocatechin 3-Gallate Neuroprotective Action

Activation of a Novel Injury-Induced Calcium-Permeable Channel That Plays a Key Role in Causing Extended Neuronal Depolarization and Initiating Neuronal Death in Excitotoxic Neuronal Injury

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