Cited by 770Nitric Oxide and Endothelin EffectsProtein Kinase Regulation and GTPase SignalingCardiovascular Health and Disease Prevention

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Phosphorylation of Thr 495 Regulates Ca 2+ /Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity

Fleming, Ingrid, Fisslthaler, Beate, Dimmeler, Stefanie, Kemp, Bruce E., Busse, Rudi·2001·Circulation Research

DOI 10.1161/hh1101.092677

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Abstract

Abstract —The activity of the endothelial nitric oxide synthase (eNOS) can be regulated independently of an increase in Ca 2+ by the phosphorylation of Ser 1177 but results only in a low nitric oxide (NO) output. In the present study, we assessed whether the agonist-induced (Ca 2+ -dependent, high-output) activation of eNOS is associated with changes in the phosphorylation of Thr 495 in the calmodulin (CaM)-binding domain. eNOS Thr 495 was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation. In the same cells, bradykinin enhanced the phosphorylation of Ser 1177 , which was maximal after 5 minutes, and abolished by the CaM-dependent kinase II (CaMKII) inhibitor KN-93. Bradykinin also enhanced the association of CaMKII with eNOS. Phosphorylation of Thr 495 was attenuated by the protein kinase C (PKC) inhibitor Ro 31-8220 and after PKC downregulation using phorbol 12-myristate 13-acetate. The agonist-induced dephosphorylation of Thr 495 was completely Ca 2+ -dependent and inhibited by the PP1 inhibitor calyculin A. Little CaM was bound to eNOS immunoprecipitated from unstimulated cells, but the agonist-induced dephosphorylation of Thr 495 enhanced the association of CaM. Mutation of Thr 495 to alanine increased CaM binding to eNOS in the absence of cell stimulation, whereas the corresponding Asp 495 mutant bound almost no CaM. Accordingly, NO production by the Ala 495 mutant was more sensitive to Ca 2+ /CaM than the aspartate mutant. These results suggest that the dual phosphorylation of Ser 1177 and Thr 495 determines the activity of eNOS in agonist-stimulated endothelial cells. Moreover, the dephosphorylation of Thr 495 by PP1 precedes the phosphorylation of Ser 1177 by CaMKII. The full text of this article is available at http://www.circresaha.org.

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“We also demonstrated a downregulation of the Pi-NOS-3 495, a site recognized for inactivation of NOS ( Fleming et al. 2001 ).”
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“The NOS isoforms are phosphorylated by various kinases such as cyclic AMP-dependents protein kinase, cyclic GMP-dependents protein kinase, protein kinase C, or Ca2＋/calmodulin-dependent protein kinase (Nathan and Xie, 1994; Sase and Michel, 1997; Fleming et al., 2001).”
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Activation of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II in response to Morris water maze learning in rats
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“It is worth noting that neuronal NOS can be regulated via phosphorylation by CaM-kinase II (Agostino et al., 2004; Fleming et al., 2001; Komeima et al., 2000).”
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“Thr497 is a negative regulatory site of eNOS activity, PKC or AMPK can phosphorylate eNOS-Thr 497 which leads to the inactivation of the enzyme [ 14 ,15,21] .”
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Endothelin-1 acutely increases nitric oxide production via the calcineurin mediated dephosphorylation of Caveolin-1
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Modulation of nNOS ser852 phosphorylation and translocation by PKA/PP1 pathway in endothelial cells
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Fructose-rich diet and insulin action in female rat heart: Estradiol friend or foe?
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Authors: Fleming, I., Fisslthaler, B., Dimmeler, S., Kemp, B. E., & Busse, R.
Affiliations: Goethe University Frankfurt (DE)
ORCID: Fleming, Ingrid
Fisslthaler, Beate
Dimmeler, Stefanie
Kemp, Bruce E.
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2001-06-08
Volume: 88
Issue: 11
Pages: E68-75
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/hh1101.092677
OpenAlex: W2135297555
Cited by: 770
References: 38
Citations by year: 2026: 12 · 2025: 25 · 2024: 13 · 2023: 17 · 2022: 17 · 2021: 23 · 2020: 18 · 2019: 23 · 2018: 18 · 2017: 29 · 2016: 30 · 2015: 39 · 2014: 34 · 2013: 28 · 2012: 49
FWCI: 23.32
Type: journal article
Language: en
Open access: closed
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart Foundation of Australia
Deutsche Forschungsgemeinschaft (SFB 553)
Medical Research Council
National Health and Medical Research Council
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords: endothelial nitric oxide synthase, calmodulin binding, CaMKII, PP1 phosphatase, calyculin A, bradykinin, protein kinase C, nitric oxide production, endothelial cells, dual phosphorylation, calmodulin-dependent kinase II, calmodulin
MeSH terms: Animals, Binding Sites, Bradykinin, Calcium, Calmodulin, Cells, Cultured, Coronary Vessels, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Humans, Phosphorylation, Precipitin Tests, Protein Kinase C, Proto-Oncogene Proteins, Swine, Threonine, Blotting, Western, Mutagenesis, Site-Directed, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Nitric Oxide Synthase, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques

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Phosphorylation of Thr 495 Regulates Ca 2+ /Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity

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