Neuronal nitric oxide synthase (nNOS) modulates the JNK1 activity through redox mechanism: A cGMP independent pathway

Hee S. Park, Sung H. Huh, Mi Sung Kim, Doo Yeon Kim, Byoung Joo Gwag, Ssang G. Cho, Eui Ju Choi

Research output: Contribution to journalArticle

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Abstract

Nitric oxide (NO) is a small, uncharged molecule, which is primarily generated by the nitric oxide synthase (NOS) family of proteins, including neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO has been implicated in diverse roles in biological systems, such as the regulation of cell death and survival signaling pathways of a variety of cell types, including neuronal cells. In this study, we determined that the NO generated from l-arginine by ectopically overexpressed nNOS in HEK293 cells exerted an inhibitory effect against the activity of c-Jun N-terminal kinase (JNK), an important modulator of neuronal cell death and survival signaling pathways. NO repressed the activation of JNK, but exerted no significant effects on the activities of SEK1/MKK4 and MEKK1, which are the upstream MAPKK and MAPKKK of JNK1, respectively. This NO-mediated inhibition of JNK1 was not affected by the addition of ODQ, a guanylyl cyclase inhibitor, indicating that the effect is independent of the level of cyclic GMP. In an in vitro kinase assay, SNAP, a NO donor, was shown to directly suppress JNK1 activity, thereby indicating that NO is a direct modulator of JNK1. Moreover, the NO-mediated suppression of JNK1 was demonstrated to be redox-sensitive and dependent on the cysteine-116 in JNK1. Finally, according to the results of an immunohistochemical study using rat striatal neurons, we were able to determine that nNOS-expressing neurons evidenced significantly reduced JNK1 activation. Collectively, these data suggest that JNK1 is regulated by nNOS-mediated NO production in neurons, via a thiol-redox-sensitive mechanism.

Original languageEnglish
Pages (from-to)408-414
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume346
Issue number2
DOIs
Publication statusPublished - 2006 Jul 28

Fingerprint

Nitric Oxide Synthase Type I
Oxidation-Reduction
Nitric Oxide
Neurons
JNK Mitogen-Activated Protein Kinases
Cell death
Modulators
Cell Survival
Cell Death
Chemical activation
MAP Kinase Kinase Kinases
Corpus Striatum
Nitric Oxide Donors
Nitric Oxide Synthase Type III
HEK293 Cells
Guanylate Cyclase
Mitogen-Activated Protein Kinase Kinases
Cyclic GMP
Nitric Oxide Synthase Type II
Biological systems

Keywords

  • c-Jun N-terminal kinase
  • Guanylyl cyclase
  • nNOS
  • Redox

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Neuronal nitric oxide synthase (nNOS) modulates the JNK1 activity through redox mechanism : A cGMP independent pathway. / Park, Hee S.; Huh, Sung H.; Kim, Mi Sung; Kim, Doo Yeon; Gwag, Byoung Joo; Cho, Ssang G.; Choi, Eui Ju.

In: Biochemical and Biophysical Research Communications, Vol. 346, No. 2, 28.07.2006, p. 408-414.

Research output: Contribution to journalArticle

Park, Hee S. ; Huh, Sung H. ; Kim, Mi Sung ; Kim, Doo Yeon ; Gwag, Byoung Joo ; Cho, Ssang G. ; Choi, Eui Ju. / Neuronal nitric oxide synthase (nNOS) modulates the JNK1 activity through redox mechanism : A cGMP independent pathway. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 346, No. 2. pp. 408-414.
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abstract = "Nitric oxide (NO) is a small, uncharged molecule, which is primarily generated by the nitric oxide synthase (NOS) family of proteins, including neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO has been implicated in diverse roles in biological systems, such as the regulation of cell death and survival signaling pathways of a variety of cell types, including neuronal cells. In this study, we determined that the NO generated from l-arginine by ectopically overexpressed nNOS in HEK293 cells exerted an inhibitory effect against the activity of c-Jun N-terminal kinase (JNK), an important modulator of neuronal cell death and survival signaling pathways. NO repressed the activation of JNK, but exerted no significant effects on the activities of SEK1/MKK4 and MEKK1, which are the upstream MAPKK and MAPKKK of JNK1, respectively. This NO-mediated inhibition of JNK1 was not affected by the addition of ODQ, a guanylyl cyclase inhibitor, indicating that the effect is independent of the level of cyclic GMP. In an in vitro kinase assay, SNAP, a NO donor, was shown to directly suppress JNK1 activity, thereby indicating that NO is a direct modulator of JNK1. Moreover, the NO-mediated suppression of JNK1 was demonstrated to be redox-sensitive and dependent on the cysteine-116 in JNK1. Finally, according to the results of an immunohistochemical study using rat striatal neurons, we were able to determine that nNOS-expressing neurons evidenced significantly reduced JNK1 activation. Collectively, these data suggest that JNK1 is regulated by nNOS-mediated NO production in neurons, via a thiol-redox-sensitive mechanism.",
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T1 - Neuronal nitric oxide synthase (nNOS) modulates the JNK1 activity through redox mechanism

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AU - Park, Hee S.

AU - Huh, Sung H.

AU - Kim, Mi Sung

AU - Kim, Doo Yeon

AU - Gwag, Byoung Joo

AU - Cho, Ssang G.

AU - Choi, Eui Ju

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N2 - Nitric oxide (NO) is a small, uncharged molecule, which is primarily generated by the nitric oxide synthase (NOS) family of proteins, including neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO has been implicated in diverse roles in biological systems, such as the regulation of cell death and survival signaling pathways of a variety of cell types, including neuronal cells. In this study, we determined that the NO generated from l-arginine by ectopically overexpressed nNOS in HEK293 cells exerted an inhibitory effect against the activity of c-Jun N-terminal kinase (JNK), an important modulator of neuronal cell death and survival signaling pathways. NO repressed the activation of JNK, but exerted no significant effects on the activities of SEK1/MKK4 and MEKK1, which are the upstream MAPKK and MAPKKK of JNK1, respectively. This NO-mediated inhibition of JNK1 was not affected by the addition of ODQ, a guanylyl cyclase inhibitor, indicating that the effect is independent of the level of cyclic GMP. In an in vitro kinase assay, SNAP, a NO donor, was shown to directly suppress JNK1 activity, thereby indicating that NO is a direct modulator of JNK1. Moreover, the NO-mediated suppression of JNK1 was demonstrated to be redox-sensitive and dependent on the cysteine-116 in JNK1. Finally, according to the results of an immunohistochemical study using rat striatal neurons, we were able to determine that nNOS-expressing neurons evidenced significantly reduced JNK1 activation. Collectively, these data suggest that JNK1 is regulated by nNOS-mediated NO production in neurons, via a thiol-redox-sensitive mechanism.

AB - Nitric oxide (NO) is a small, uncharged molecule, which is primarily generated by the nitric oxide synthase (NOS) family of proteins, including neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO has been implicated in diverse roles in biological systems, such as the regulation of cell death and survival signaling pathways of a variety of cell types, including neuronal cells. In this study, we determined that the NO generated from l-arginine by ectopically overexpressed nNOS in HEK293 cells exerted an inhibitory effect against the activity of c-Jun N-terminal kinase (JNK), an important modulator of neuronal cell death and survival signaling pathways. NO repressed the activation of JNK, but exerted no significant effects on the activities of SEK1/MKK4 and MEKK1, which are the upstream MAPKK and MAPKKK of JNK1, respectively. This NO-mediated inhibition of JNK1 was not affected by the addition of ODQ, a guanylyl cyclase inhibitor, indicating that the effect is independent of the level of cyclic GMP. In an in vitro kinase assay, SNAP, a NO donor, was shown to directly suppress JNK1 activity, thereby indicating that NO is a direct modulator of JNK1. Moreover, the NO-mediated suppression of JNK1 was demonstrated to be redox-sensitive and dependent on the cysteine-116 in JNK1. Finally, according to the results of an immunohistochemical study using rat striatal neurons, we were able to determine that nNOS-expressing neurons evidenced significantly reduced JNK1 activation. Collectively, these data suggest that JNK1 is regulated by nNOS-mediated NO production in neurons, via a thiol-redox-sensitive mechanism.

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