Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation

Mount, Peter F.; Kemp, Bruce E.; Power, David A.

doi:10.1016/j.yjmcc.2006.05.023

Cited by 498Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionProtein Kinase Regulation and GTPase Signaling

Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation

Mount, Peter F., Kemp, Bruce E., Power, David A.·2007·Journal of Molecular and Cellular Cardiology

DOI 10.1016/j.yjmcc.2006.05.023

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Abstract

The controlled regulation of nitric oxide (NO) synthesis in endothelial cells and cardiomyocytes by the endothelial form of nitric oxide synthase (eNOS or NOS3) is essential for cardiovascular health. In recent years, a picture of complex and precise regulation of eNOS activity involving multi-site phosphorylation of specific serine and threonine residues has emerged. Regulation of endothelial NO synthesis by multi-site eNOS phosphorylation occurs in response to a wide variety of humoral, mechanical and pharmacological stimuli. This regulation involves numerous kinases and phosphatases, as well as interactions with other aspects of eNOS regulation such as Ca(2+) flux, protein-protein interactions and regulation of subcellular localization. Phosphorylation of eNOS-Ser(1177) close to the carboxy-terminal is a critical requirement for eNOS activation. In addition, phosphorylation of eNOS-Ser(633) in the flavin mononucleotide (FMN) binding domain also increases eNOS activity and appears particularly important for the maintenance of NO synthesis after initial activation by Ca(2+) flux and Ser(1177) phosphorylation. In contrast, NO synthesis is inhibited by phosphorylation of eNOS-Thr(495), which interferes with the binding of calmodulin to the eNOS calmodulin-binding domain. Regulated phosphorylation of eNOS also occurs at eNOS-Ser(114) and eNOS-Ser(615); however, the functions of these phosphorylation sites remain controversial. This review summarizes the present knowledge of the regulation of NO synthesis by multi-site eNOS phosphorylation and its relationship to other mechanisms of eNOS regulation. This progress in understanding important mechanisms controlling endothelial NO synthesis creates new opportunities to understand and potentially treat cardiovascular diseases characterized by deficient NO synthesis.

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ADMA is mainly produced from the breakdown of proteins containing methylated arginine residues.
“ADMA (FIGURE 3) is mainly produced from the breakdown of proteins containing methylated arginine residues.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [668]
In recent years, it has become clear that extracellular l-arginine and ADMA concentrations, compartmentalization, and membrane transporters are important for NOS function.
“However, in recent years, it has become clear that extracellular l-arginine and ADMA concentrations, compartmentalization, and membrane transporters are important for NOS function, as will be discussed below in sect. IIIB4 (167, 668, 1030).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [668]
The involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes.
“It seems that the involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes (668, 857, 1029).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [668]

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Analysis of Neuronal Nitric Oxide Synthase Isoform Expression and Identification of Human nNOS-μ
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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THE STUDY ON THE ROLE OF THE SUBSTRATE,INHIBITOR OF NOS AND PROVIDER OF NO IN RABBITS' INFECTION BY EIMERIA STIEDAI
Zhang, X. (2008) · Shandong Nongye Daxue xuebao

Authors: Mount, P. F., Kemp, B. E., & Power, D. A.
Affiliations: Burnet Institute (AU)
Commonwealth Scientific and Industrial Research Organisation (AU)
Corresponding author: Mount, Peter F.
ORCID: Mount, Peter F.
Kemp, Bruce E.
Power, David A.
Venue: Journal of Molecular and Cellular Cardiology
Publisher: Elsevier BV
Published: 2007-02
Volume: 42
Issue: 2
Pages: 271-279
ISSN: 0022-2828 (ISSN-L)
DOI: 10.1016/j.yjmcc.2006.05.023
OpenAlex: W2047770461
Cited by: 498
References: 72
Citations by year: 2026: 5 · 2025: 10 · 2024: 16 · 2023: 11 · 2022: 15 · 2021: 24 · 2020: 24 · 2019: 25 · 2018: 18 · 2017: 16 · 2016: 24 · 2015: 38 · 2014: 45 · 2013: 34 · 2012: 58
FWCI: 3.03
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Journal of Molecular and Cellular Cardiology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: endothelial nitric oxide synthase, nitric oxide synthase, nitric oxide production, multisite phosphorylation, calmodulin binding, cardiomyocytes, endothelial cells, cardiovascular disease
MeSH terms: Animals, Cardiovascular Diseases, Endothelium, Vascular, Humans, Myocardium, Nitric Oxide, Phosphorylation, Protein Processing, Post-Translational, Nitric Oxide Synthase Type III

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Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation

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