Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning

Aras, Mandar A.; Hara, Hirokazu; Hartnett, Karen A.; Kandler, Karl; Aizenman, Elias

doi:10.1111/j.1471-4159.2009.06106.x

Cited by 56 publications

(83 citation statements)

References 51 publications

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“…Although numerous studies have suggested that various PKC isoforms are involved in neuronal survival and death (Aras et al, 2009;Miller et al, 2009;Nelson and Alkon, 2009), the role of PKCs in oxidative stress induced toxicity to OLs has not been elucidated. In this study, we found that PKCs are important signaling proteins involved in the cell death pathways triggered by the potent oxidant, peroxynitrite.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Lin

Tchantchou

et al. 2011

Molecular and Cellular Neuroscience

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Peroxynitrite has been suggested to be the potent oxidant causing toxicity to neurons and oligodendrocytes (OLs). Our previous studies have illustrated that intracellular zinc liberation contributes to peroxynitrite toxicity to mature OLs. In this study, we further investigated the signaling pathways involved in this event and identified protein kinase C (PKC) as an important early signaling molecule. We found that a non-selective PKC inhibitor bisindolylmaleimide-1 blocked OL toxicity induced by a peroxynitrite generator SIN-1 and exogenous zinc. The protective effects were due to its inhibition on ERK1/2 phosphorylation and ROS generation. The same phenomenon was also observed in OLs following prolonged treatment with phorbol 12 myristate 13 acetate (PMA), which downregulates the conventional and the novel PKC isoforms (cPKCs and nPKCs). To determine the role of specific PKC isoforms, we found that a specific nPKC inhibitor rottlerin significantly reduced SIN-1-or zinc-induced toxicity, whereas Go6976, a cPKC inhibitor, reduced OL toxicity triggered by zinc, but not by SIN-1 at high concentrations. Rottlerin was more potent than Go6976 to attenuate ERK1/2 phosphorylation and ROS generation induced by SIN-1 or zinc. Surprisingly, zinc only induced phosphorylation of PKCθ, but not PKCδ. Knockdown of PKCθ using lentiviral shRNA attenuated SIN-1-or zinc-induced toxicity. These results suggest that PKCθ might be the major PKC isoform involved in peroxynitrite and zinc toxicity to mature OLs, and provide a rationale for development of specific inhibitors of PKCθ in the treatment of multiple sclerosis and other neurodegenerative diseases, in which peroxynitrite formation plays a pathogenic role.Published by Elsevier Inc.

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Section: Discussionmentioning

confidence: 99%

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Lin

Tchantchou

et al. 2011

Molecular and Cellular Neuroscience

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“…In several animal models of cerebral ischemia, Zn 2þ chelation has consistently been shown to reduce neuronal death (16,53). However, emerging in vivo and in vitro studies suggest that a sublethal increase in neuronal free Zn 2þ may also trigger pathways that limit cell injury after injury and confer longterm tolerance (5,65). The mechanisms accounting for the free Zn 2þ accumulation and downstream signaling pathways mediating neuroprotection may provide novel therapeutic targets for regulating intracellular Zn 2þ signals, and ultimately cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence suggests that preconditioning stimuli induce the sublethal activation of cell death factors that trigger survival pathways, which, in turn, prevent subsequent lethal injurious signaling (32). Along these lines, a novel role for Zn 2þ as an important, early signal in the initiation of survival pathways critical to neuronal tolerance has emerged (5,65). The results from these studies offer insights into endogenous mechanisms that protect neurons in the face of lethal cellular injury.…”

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confidence: 90%

“…Until recently, the intracellular accumulation of free Zn 2þ has been largely identified as a characteristic of degenerating neurons. Using in vivo and in vitro systems, two recent reports have shown that a sublethal stimulus led to an accumulation of free Zn 2þ in preconditioned neurons (5,65). The free Zn 2þ rise occurred immediately after the preconditioning stimulus, subsided 24 h after the sublethal stimulus, and was required for neuronal tolerance (5,65).…”

Section: Zinc Accumulation In Preconditioned Neuronsmentioning

confidence: 99%

“…Using in vivo and in vitro systems, two recent reports have shown that a sublethal stimulus led to an accumulation of free Zn 2þ in preconditioned neurons (5,65). The free Zn 2þ rise occurred immediately after the preconditioning stimulus, subsided 24 h after the sublethal stimulus, and was required for neuronal tolerance (5,65). The increase in neuronal free Zn 2þ activated caspase-3-dependent PARP-1 cleavage, HSP70 upregulation, and Zn 2þ -regulated gene transcription conferring delayed neuronal tolerance (Fig.…”

Section: Zinc Accumulation In Preconditioned Neuronsmentioning

confidence: 99%

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Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

Aras

Aizenman

2011

Antioxidants & Redox Signaling

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Zn2+ has emerged as a major regulator of neuronal physiology, as well as an important signaling agent in neural injury. The intracellular concentration of this metal is tightly regulated through the actions of Zn 2+ transporters and the thiol-rich metal binding protein metallothionein, closely linking the redox status of the cell to cellular availability of Zn 2+ . Accordingly, oxidative and nitrosative stress during ischemic injury leads to an accumulation of neuronal free Zn 2+ and the activation of several downstream cell death processes. While this Zn 2+ rise is an established signaling event in neuronal cell death, recent evidence suggests that a transient, sublethal accumulation of free Zn 2+ can also play a critical role in neuroprotective pathways activated during ischemic preconditioning. Thus, redox-sensitive proteins, like metallothioneins, may play a critical role in determining neuronal cell fate by regulating the localization and concentration of intracellular free Zn 2+

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Erratum

2008

Arthritis Rheum

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Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning

Abstract: Abbreviations used: KCN, potassium cyanide; MRE, metal response element; MT, metallothionein; MTF-1, metal response element transcription factor-1; PKC, protein kinase C; shRNA, short hairpin RNA; TPEN, N,N,N¢,N¢-tetrakis (2-pyridalmethyl)ethylenediamine.

Cited by 56 publications

References 51 publications

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

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