Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide
Abstract
Nitric oxide (NO) is a potent cell-signaling, effector, and vasodilator molecule that plays important roles in diverse biological effects in the kidney, vasculature, and many other tissues. Because of its high biological reactivity and diffusibility, multiple tiers of regulation, ranging from transcriptional to posttranslational controls, tightly control NO biosynthesis. Interactions of each of the major NO synthase (NOS) isoforms with heterologous proteins have emerged as a mechanism by which the activity, spatial distribution, and proximity of the NOS isoforms to regulatory proteins and intended targets are governed. Dimerization of the NOS isozymes, required for their activity, exhibits distinguishing features among these proteins and may serve as a regulated process and target for therapeutic intervention. An increasingly wide array of proteins, ranging from scaffolding proteins to membrane receptors, has been shown to function as NOS-binding partners. Neuronal NOS interacts via its PDZ domain with several PDZ-domain proteins. Several resident and recruited proteins of plasmalemmal caveolae, including caveolins, anchoring proteins, G protein-coupled receptors, kinases, and molecular chaperones, modulate the activity and trafficking of endothelial NOS in the endothelium. Inducible NOS (iNOS) interacts with the inhibitory molecules kalirin and NOS-associated protein 110 kDa, as well as activator proteins, the Rac GTPases. In addition, protein-protein interactions of proteins governing iNOS transcription function to specify activation or suppression of iNOS induction by cytokines. The calpain and ubiquitin-proteasome pathways are the major proteolytic systems responsible for the regulated degradation of NOS isozymes. The experimental basis for these protein-protein interactions, their functional importance, and potential implication for renal and vascular physiology and pathophysiology is reviewed.
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Three distinct NOS isoforms have been identified, all of which have different characteristics and generate NO at different rates.
“Three distinct isoforms have been identified, all of which have different characteristics and generate NO at different rates (27).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [27]
Neuronal NOS is a Ca2+/calmodulin-dependent isoform that, in the brain, is activated physiologically by agonists of the N-methyl-d-aspartate receptor.
“It is also a Ca2+/calmodulin-dependent isoform that, in the brain, is activated physiologically by agonists of the N-methyl-d-aspartate receptor (27).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [27]
Inducible NOS is expressed in multiple cell types in response to inflammatory stimuli such as endotoxin and cytokines.
“This isoform is expressed in multiple cell types in response to inflammatory stimuli such as that induced by endotoxin and cytokines, e.g. interleukin-1 and -2, tumor necrosis factor-α, and interferon-γ (27, 32).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [27]
Regulation of eNOS is intimately related to physical forces important in vascular function such as shear stress induced by blood flow.
“Regulation of eNOS is also intimately related to the physical forces important in vascular function such as shear stress induced by blood flow (27, 31).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [27]
NOS enzymes are regulated by post-translational modifications, controlled localization within the cell, substrate and cofactor availability, and other proteins with which they form stable complexes.
“The NOS enzymes are regulated by post-translational modifications, controlled localization within the cell, substrate and cofactor availability, and other proteins with which they form stable complexes (27).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [27]
NOS2 has the highest capacity to generate NO and is expressed in multiple cell types in response to inflammatory stimuli.
“NOS2 (also termed inducible NOS or iNOS), which has the highest capacity to generate NO, is expressed in multiple cell types in response to inflammatory stimuli [75, 76].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [75]
NOS3 produces relatively low quantities of NO, and its activity is controlled by calcium/calmodulin, post-translational modifications, and physical forces such as shear stress.
“It produces relatively low quantities of NO, and its activity is controlled by Ca2+ and calmodulin, post-translational modifications [72, 73], and physical forces such as shear stress [74, 75].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [75]
NOS1 is a calcium/calmodulin-dependent isoform that can be activated by agonists of the NMDA receptor.
“NOS1 (frequently called neuronal NOS or nNOS) is also a Ca2+/calmodulin-dependent isoform that can be activated by agonists of the N-methyl-D-aspartate (NMDA) receptor [75].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [75]
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References 108 · Cited by 305
- Authors
- Kone, B. C., Kuncewicz, T., Zhang, W., & Yu, Z.-Y.
- Affiliations
- Departments of Internal Medicine and Integrative Biology, Pharmacology, and Physiology, The University of Texas Medical School at Houston, Houston, Texas 77030
- ORCID
- Zhang, Wenzheng
- Venue
- American Journal of Physiology-Renal Physiology
- Publisher
- American Physiological Society
- Published
- 2003-08
- Volume
- 285
- Issue
- 2
- Pages
- F178-F190
- ISSN
- 1522-1466 (ISSN-L)
- 1931-857X
- OpenAlex
- W2170181181
- Cited by
- 305
- References
- 108
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 6 · 2023: 13 · 2022: 8 · 2021: 9 · 2020: 13 · 2019: 9 · 2018: 4 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 14 · 2013: 8 · 2012: 21
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Renal Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- nitric oxide synthase, protein-protein interaction, neuronal NOS, endothelial NOS, inducible nitric oxide synthase, PDZ domain, caveolae, caveolin, Kalirin, Rac GTPase, calpain, ubiquitin-proteasome system, renal physiology, vascular physiology
- MeSH terms
- Animals, Calmodulin, Humans, Nitric Oxide, HSP90 Heat-Shock Proteins, Nitric Oxide Synthase, rac GTP-Binding Proteins
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