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Cited by 979Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressHemoglobin structure and function

The chemical biology of nitric oxide: Implications in cellular signaling

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Thomas, Douglas D., Ridnour, Lisa A., Isenberg, Jeffrey S., Flores-Santana, Wilmarie, Switzer, Christopher H., Donzelli, Sonia, Hussain, Perwez, Vecoli, Cecilia +6 more·2008·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2008.03.020PMC PMC2572721
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Abstract

Nitric oxide (NO) has earned the reputation of being a signaling mediator with many diverse and often opposing biological activities. The diversity in response to this simple diatomic molecule comes from the enormous variety of chemical reactions and biological properties associated with it. In the past few years, the importance of steady-state NO concentrations has emerged as a key determinant of its biological function. Precise cellular responses are differentially regulated by specific NO concentration. We propose five basic distinct concentration levels of NO activity: cGMP-mediated processes ([NO]<1-30 nM), Akt phosphorylation ([NO] = 30-100 nM), stabilization of HIF-1alpha ([NO] = 100-300 nM), phosphorylation of p53 ([NO]>400 nM), and nitrosative stress (1 microM). In general, lower NO concentrations promote cell survival and proliferation, whereas higher levels favor cell cycle arrest, apoptosis, and senescence. Free radical interactions will also influence NO signaling. One of the consequences of reactive oxygen species generation is to reduce NO concentrations. This antagonizes the signaling of nitric oxide and in some cases results in converting a cell-cycle arrest profile to a cell survival profile. The resulting reactive nitrogen species that are generated from these reactions can also have biological effects and increase oxidative and nitrosative stress responses. A number of factors determine the formation of NO and its concentration, such as diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. These are the chemical and biochemical parameters that shape cellular responses to NO. Herein we discuss signal transduction and the chemical biology of NO in terms of the direct and indirect reactions.

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  • Most ROS/RNS molecules, despite being long considered toxic, have been shown to exert important signaling functions.

    “It is worth indicating that despite being long considered toxic species, most of these molecules have been shown to exert important signaling functions”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [937]

  • Redox active molecules also act as signaling agents controlling physiological functions and coordinating inflammatory and tissue restoration mechanisms.

    “However, redox active molecules also serve as signaling agents for control of a variety of physiological functions as well as coordination of inflammatory and tissue restoration mechanisms [2].”

    From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [2]

  • In cytokine-stimulated breast cancer cells, downstream NO-mediated signaling correlates with an ~300 nM NO flux, compared to ~1-10 μM in activated murine macrophages.

    “However, in cytokine stimulated breast cancer cells, downstream NO-mediated signaling pathways correlated with an ~300 nM NO flux, in comparison to ~1-10 μM in activated murine macrophages [2].”

    From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [2]

  • Nitrosation, nitration and oxidation can be initiated by several mechanisms, including NO autoxidation, protonation of nitrite, reaction of NO with superoxide, and metal-mediated processes, all of which play critical roles in different cellular compartments.

    “These include NO autoxidation, protonation of nitrite, reaction of NO with O2− and metal mediated processes (Figure 3), all of which play critical roles in different compartments in cells and tissue [2].”

    From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [2]

  • S-Nitrosothiols take part in both enzymatic and non-enzymatic reactions.

    “S-Nitrosothiols can participate in a variety of reactions, both enzymatic and non-enzymatic [2].”

    From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [2]

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  1. [21]Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med. 1998;25:434–456. doi: 10.1016/s0891-5849(98)00092-6. [[DOI](https://doi.org/10.1016/s0891-5849(98)00092-6)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9741580/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Free%20Radic%20Biol%20Med&title=Chemical%20biology%20of%20nitric%20oxide:%20Insights%20into%20regulatory,%20cytotoxic,%20and%20cytoprotective%20mechanisms%20of%20nitric%20oxide&author=DA%20Wink&author=JB%20Mitchell&volume=25&publication_year=1998&pages=434-456&pmid=9741580&doi=10.1016/s0891-5849(98)00092-6&)] · DOI · Paper page
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Authors
Thomas, D. D., Ridnour, L. A., Isenberg, J. S., Flores-Santana, W., Switzer, C. H., Donzelli, S., Hussain, P., Vecoli, C., Paolocci, N., Ambs, S., Colton, C. A., Harris, C. C., Roberts, D. D., & Wink, D. A.
Affiliations
  • University of Illinois Chicago (US)
  • National Institutes of Health (US)
  • Johns Hopkins University (US)
  • Duke University (US)
Corresponding author
Wink, David A.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2008-07
Volume
45
Issue
1
Pages
18-31
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2008.03.020
PMC
PMC2572721
OpenAlex
W1980458823
Cited by
975
References
166
Citations by year
2026: 33 · 2025: 44 · 2024: 37 · 2023: 54 · 2022: 57 · 2021: 73 · 2020: 58 · 2019: 55 · 2018: 54 · 2017: 45 · 2016: 53 · 2015: 63 · 2014: 67 · 2013: 50 · 2012: 69
FWCI
5.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (K22CA113315, Z01BC010033)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
nitric oxide, signal transduction, NO concentration, cGMP signaling, Akt phosphorylation, HIF-1α stabilization, p53 phosphorylation, nitrosative stress, reactive oxygen species, reactive nitrogen species, oxidative stress, cell cycle arrest, apoptosis, senescence
MeSH terms
Animals, Diffusion, Humans, Kinetics, Nitric Oxide, Signal Transduction

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