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Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation
Open accessAbstract
Endothelial nitric-oxide synthase (eNOS) is phosphorylated at Ser-1179 (bovine sequence) by Akt after growth factor or shear stress stimulation of endothelial cells, resulting in increased eNOS activity. Purified eNOS is also phosphorylated at Thr-497 by purified AMP-activated protein kinase, resulting in decreased eNOS activity. We investigated whether bradykinin (BK) stimulation of bovine aortic endothelial cells (BAECs) regulates eNOS through Akt activation and Ser-1179 or Thr-497 phosphorylation. Akt is transiently activated in BK-stimulated BAECs. Activation is blocked completely by wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase, suggesting that Akt activation occurs downstream from phosphatidylinositol 3-kinase. BK stimulates a transient phosphorylation of eNOS at Ser-1179 that is correlated temporally with a transient dephosphorylation of eNOS at Thr-497. Phosphorylation at Ser-1179, but not dephosphorylation at Thr-497, is blocked by wortmannin and LY294002. BK also stimulates a transient nitric oxide (NO) release from BAECs with a time-course similar to Ser-1179 phosphorylation and Thr-497 dephosphorylation. NO release is not altered by wortmannin. BK-stimulated dephosphorylation of Thr-497 and NO release are blocked by the calcineurin inhibitor, cyclosporin A. These data suggest that BK activation of eNOS in BAECs primarily involves deinhibition of the enzyme through calcineurin-mediated dephosphorylation at Thr-497.
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“Phosphorylation of Thr495 is a negative regulator of CaM binding to eNOS (297, 407, 646).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [407]
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Metadata
- Authors
- Harris, M. B., Ju, H., Venema, V. J., Liang, H., Zou, R., Michell, B. J., Chen, Z.-P., Kemp, B. E., & Venema, R. C.
- Affiliations
- Augusta University (US)
- Center for Vascular Biology Research (US)
- St Vincents Institute of Medical Research (AU)
- Corresponding author
- Venema, Richard C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-05
- Volume
- 276
- Issue
- 19
- Pages
- 16587-16591
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2144179854
- Cited by
- 363
- References
- 29
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 9 · 2021: 10 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 9 · 2014: 13 · 2013: 16 · 2012: 16
- FWCI
- 18.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-62152, R01HL062152, HL57201)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Hematology › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- endothelial nitric oxide synthase, bradykinin, Akt, phosphatidylinositol 3-kinase, calcineurin, cyclosporine, nitric oxide release, endothelial cells, enzyme regulation
- MeSH terms
- Wortmannin, Androstadienes, Animals, Aorta, Bradykinin, Cattle, Chromones, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Kinetics, Morpholines, Phosphorylation, Phosphoserine, Phosphothreonine, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Cyclosporine, Protein Serine-Threonine Kinases, Nitric Oxide Synthase, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, Calcineurin Inhibitors
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