Inhibition of NMDA-induced protein kinase C translocation by a Zn2+ chelator: Implication of intracellular Zn2+

Baba, Akemichi; Etoh, Susumu; Iwata, Hisato

doi:10.1016/0006-8993(91)90121-b

Cited by 33 publications

(7 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A potential candidate for a target for TPEN in mediating PARS‐independent cytoprotection may be another zinc finger protein family, namely the protein kinase C (PKC) family. Although the effect of peroxynitrite on kinase signalling pathways has not yet been investigated, superoxide and nitric oxide have been shown to be involved in N‐methyl‐ D ‐aspartate receptor mediated PKC activation ( Klann et al ., 1998 ) and TPEN was reported to inhibit the translocation of PKC from the cytosolic to the membranous fraction in this model ( Baba et al ., 1991 ). Moreover, hydrogen peroxide, another oxidant known to induce PARS‐activation has been shown to induce PKC activation in rat cardiac myocytes ( Sabri et al ., 1998 ), COS‐7 cells ( Konishi et al ., 1997 ) and in Jurkat T cells ( Whisler et al ., 1995 ).…”

Section: Discussionmentioning

confidence: 77%

Inhibition of poly(ADP‐ribose) synthetase (PARS) and protection against peroxynitrite‐induced cytotoxicity by zinc chelation

Virág

Szabó

1999

British J Pharmacology

View full text Add to dashboard Cite

1 Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shown to deplete cellular energy pools, leading to cell necrosis. Here we have investigated the e ect of tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) a heavy metal chelator on peroxynitrite-induced cytotoxicity. 2 TPEN (10 mM) abolished cell death induced by authentic peroxynitrite (25 mM) and the peroxynitrite generating agent 3-morpholinosidnonimine (SIN-1, 250 mM). Preincubation of TPEN with equimolar Zn 2+ but not Ca 2+ or Mg 2+ blocked the cytoprotective e ect of the chelator. 3 TPEN (10 mM) markedly reduced the peroxynitrite-induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations. 4 Although TPEN (1 ± 300 mM) did not scavenge peroxynitrite, it inhibited PARS activation in a dose-dependent manner. 5 The cytoprotective e ect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS-de®cient thymocytes from peroxynitrite-induced death. 6 While being cytoprotective against peroxynitrite-induced necrotic death, TPEN (10 mM), similar to other agents that inhibit PARS, enhanced apoptosis (at 5 ± 6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation. 7 In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective e ects against peroxynitrite-induced necrosis. Its e ects are, in part, mediated by inhibition of PARS.

show abstract

Section: Discussionmentioning

confidence: 77%

Inhibition of poly(ADP‐ribose) synthetase (PARS) and protection against peroxynitrite‐induced cytotoxicity by zinc chelation

Virág

Szabó

1999

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…The sequence that follows NMDA receptor stimulation which leads to cell death of mesencephalic dopaminergic neurons possibly includes involvement of a signal transduction system which is engaged in the change of the physiological state in cultured neurons after highfrequency stimulation by NMDNglutamate (Nicoll et al, 1988). It has been known that PKC is involved in these phenomena (Malinow et al, 1989), and PKC translocation and activation are induced by NMDA receptor stimulation (Baba et al, 1991). The protective effects of phorbol ester and gangliosides (GM, and G,,,) on GNT in mesencephalic dopamine neurons were clearly demonstrated in this study.…”

Section: Discussionmentioning

confidence: 99%

Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture

Kikuchi

Kim

1993

J of Neuroscience Research

View full text Add to dashboard Cite

The neurotoxic effect of glutamate in cultured mouse mesencephalic dopaminergic neurons was investigated. Neuron-rich cell cultures were prepared from 13-14-day-old fetal mouse ventral mesencephalic tissue. Cultures were exposed to glutamate for 10 min and evaluated for glutamate neurotoxicity (GNT) 18-24 hr later by tyrosine hydroxylase (TH) immunostaining, microtubule associated protein-2 (MAP2) immunostaining, and radiolabeled dopamine uptake assay. In glutamate-exposed cultures, the number of TH-positive neurons and the level of dopamine uptake were reduced to 40% (35-45%) and 50% (47-52%), respectively, of control cultures. The number of MAP2-positive neurons was also reduced to 47%, indicating that the GNT was not restricted or selective to dopaminergic neurons. It is concluded that GNT was mediated by the N-methyl-D-aspartic acid (NMDA) receptor from the following observations: 1) GNT was completely blocked by MK-801, an NMDA receptor antagonist; 2) NMDA itself was as toxic as glutamate; 3) 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptor, did not block GNT; 4) kainate did not show neurotoxicity at a low concentration; and 5) two modulators of the NMDA receptor, 7-chlorokynurenic acid and magnesium, were effective in blocking GNT. Protective effects of phorbol myristate acetate, a tumor promoter, and gangliosides (GM1 and GT1b) on GNT were also demonstrated. Possible interactions between GNT and several protein kinase cascades were also investigated. Forskolin, an activator of adenyl cyclase and protein kinase A, showed some protective effect on GNT. But okadaic acid, an inhibitor of phosphatases, and genistein, a tyrosine kinase inhibitor, did not show any protective effect. These results suggest that 1) glutamate is capable of causing neuronal death in the substantia nigra; 2) GNT on dopaminergic neurons is mainly mediated by the NMDA receptor under the conditions of our study; 3) protein kinase C translocation is a key mechanism of GNT; and 4) there is an interplay of a signal transduction system in the pathomechanism of GNT.

show abstract

“…Within the neuron, zinc may activate major signaling pathways including mitogenic, cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), and phosphoinositide-3 kinase-Akt/ PKB pathways (Azriel-Tamir et al, 2004;Barthel et al, 2007;Klein et al, 2002Klein et al, , 2004Malaiyandi et al, 2005;Min et al, 2007;Wä tjen et al, 2001). In particular, zinc can modulate second messenger sig-naling molecules important for neuroplasticity, such as protein kinase C and calcium/calmodulin dependent protein kinase (Baba et al, 1991;Lengyel et al, 2000). Furthermore, zinc has recently been shown to induce transactivation of the receptor tyrosine kinase B (TrkB) in cornu ammonis 3 (CA3) hippocampal cells .…”

Section: Introductionmentioning

confidence: 99%

Zinc: The brain's dark horse

Bitanihirwe

Cunningham

2009

Synapse

240

154

View full text Add to dashboard Cite

Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.

show abstract

Inhibition of NMDA-induced protein kinase C translocation by a Zn2+ chelator: Implication of intracellular Zn2+

Cited by 33 publications

References 32 publications

Inhibition of poly(ADP‐ribose) synthetase (PARS) and protection against peroxynitrite‐induced cytotoxicity by zinc chelation

Inhibition of poly(ADP‐ribose) synthetase (PARS) and protection against peroxynitrite‐induced cytotoxicity by zinc chelation

Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture

Zinc: The brain's dark horse

Contact Info

Product

Resources

About