Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons

C Centeno, M Repici, J-Y Chatton, B M Riederer, C Bonny, P Nicod, M Price, P G H Clarke, S Papa, G Franzoso, T Borsello

Research output: Contribution to journalArticle

Abstract

Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the D-retro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4), was unaffected. We then analyze the action of D-JNKI1 on four JNK targets containing a JNK-binding domain: MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells (MADD/DENN), MKK7, MKK4 and JNK-interacting protein-1 (IB1/JIP-1).

Original languageEnglish
Pages (from-to)240-253
Number of pages14
JournalCell Death and Differentiation
Volume14
Issue number2
DOIs
Publication statusPublished - 23 Jun 2006

Fingerprint

JNK Mitogen-Activated Protein Kinases
N-Methylaspartate
Neurons
MAP Kinase Kinase Kinase 4
MAP Kinase Kinase 7
MAP Kinase Kinase Kinases
Brain Ischemia
Neurodegenerative Diseases
Proteins
Phosphorylation
Peptides

Keywords

  • Adaptor Proteins, Signal Transducing/isolation & purification
  • Animals
  • Calcium/metabolism
  • Cerebral Cortex/cytology
  • Cycloheximide/pharmacology
  • Death Domain Receptor Signaling Adaptor Proteins
  • Electrophoresis, Gel, Two-Dimensional
  • Enzyme Activation/drug effects
  • Enzyme Inhibitors/pharmacology
  • Fluorescent Antibody Technique
  • Guanine Nucleotide Exchange Factors/metabolism
  • JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • MAP Kinase Kinase 4/metabolism
  • MAP Kinase Kinase 7/metabolism
  • N-Methylaspartate/toxicity
  • Neurons/cytology
  • Neurotoxins/toxicity
  • Phosphorylation/drug effects
  • Proteomics
  • Rats
  • Signal Transduction/drug effects

Cite this

Centeno, C., Repici, M., Chatton, J-Y., Riederer, B. M., Bonny, C., Nicod, P., ... Borsello, T. (2006). Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death and Differentiation, 14(2), 240-253. https://doi.org/10.1038/sj.cdd.4401988
Centeno, C ; Repici, M ; Chatton, J-Y ; Riederer, B M ; Bonny, C ; Nicod, P ; Price, M ; Clarke, P G H ; Papa, S ; Franzoso, G ; Borsello, T. / Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. In: Cell Death and Differentiation. 2006 ; Vol. 14, No. 2. pp. 240-253.
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Centeno, C, Repici, M, Chatton, J-Y, Riederer, BM, Bonny, C, Nicod, P, Price, M, Clarke, PGH, Papa, S, Franzoso, G & Borsello, T 2006, 'Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons', Cell Death and Differentiation, vol. 14, no. 2, pp. 240-253. https://doi.org/10.1038/sj.cdd.4401988

Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. / Centeno, C; Repici, M; Chatton, J-Y; Riederer, B M; Bonny, C; Nicod, P; Price, M; Clarke, P G H; Papa, S; Franzoso, G; Borsello, T.

In: Cell Death and Differentiation, Vol. 14, No. 2, 23.06.2006, p. 240-253.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons

AU - Centeno, C

AU - Repici, M

AU - Chatton, J-Y

AU - Riederer, B M

AU - Bonny, C

AU - Nicod, P

AU - Price, M

AU - Clarke, P G H

AU - Papa, S

AU - Franzoso, G

AU - Borsello, T

PY - 2006/6/23

Y1 - 2006/6/23

N2 - Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the D-retro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4), was unaffected. We then analyze the action of D-JNKI1 on four JNK targets containing a JNK-binding domain: MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells (MADD/DENN), MKK7, MKK4 and JNK-interacting protein-1 (IB1/JIP-1).

AB - Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the D-retro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4), was unaffected. We then analyze the action of D-JNKI1 on four JNK targets containing a JNK-binding domain: MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells (MADD/DENN), MKK7, MKK4 and JNK-interacting protein-1 (IB1/JIP-1).

KW - Adaptor Proteins, Signal Transducing/isolation & purification

KW - Animals

KW - Calcium/metabolism

KW - Cerebral Cortex/cytology

KW - Cycloheximide/pharmacology

KW - Death Domain Receptor Signaling Adaptor Proteins

KW - Electrophoresis, Gel, Two-Dimensional

KW - Enzyme Activation/drug effects

KW - Enzyme Inhibitors/pharmacology

KW - Fluorescent Antibody Technique

KW - Guanine Nucleotide Exchange Factors/metabolism

KW - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors

KW - MAP Kinase Kinase 4/metabolism

KW - MAP Kinase Kinase 7/metabolism

KW - N-Methylaspartate/toxicity

KW - Neurons/cytology

KW - Neurotoxins/toxicity

KW - Phosphorylation/drug effects

KW - Proteomics

KW - Rats

KW - Signal Transduction/drug effects

UR - https://www.nature.com/articles/4401988

U2 - 10.1038/sj.cdd.4401988

DO - 10.1038/sj.cdd.4401988

M3 - Article

C2 - 16794604

VL - 14

SP - 240

EP - 253

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 2

ER -