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The chemical biology of nitric oxide: Implications in cellular signaling
Open accessAbstract
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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“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
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“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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“The KNO for nonheme iron systems is typically lower (~106) suggesting that a higher NO flux, in the 300 nM range, is required to significantly bind NO [2].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [2]
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- Lymar, 1995, Rapid reaction between peroxynitrite ion and carbon dioxide: implications for biological activity, J. Am. Chem. Soc., 290, 52
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Graves, D. B. (2012) · Journal of Physics D Applied Physics · doi:10.1088/0022-3727/45/26/263001 · Cited by 1,534
TNF and ROS crosstalk in inflammation
Blaser, H., Dostert, C., Mak, T. W., & Brenner, D. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.12.002 · Cited by 1,008
Application of Metal Coordination Chemistry To Explore and Manipulate Cell Biology
Haas, K. L., & Franz, K. J. (2009) · Chemical Reviews · doi:10.1021/cr900134a · Cited by 1,003
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 916
Self-citationNitric oxide and redox mechanisms in the immune response
Wink, D. A., Hines, H. B., Cheng, R. Y. S., Switzer, C. H., Flores-Santana, W., Vitek, M. P., Ridnour, L. A., & Colton, C. A. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1010550 · Cited by 765
Self-citation
Metadata
- 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)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › 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 › Biochemistry › 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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