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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“NO plays a significant role in vascular homeostasis and its bioavailability depends on several factors, including the expression level of endothelial nitric oxide synthase (eNOS) [12], the presence of substrate and cofactors for eNOS [13], the phosphorylation status of eNOS [14,15], and reaction with various reactive…”
Background
Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure
Sun, D., Cuevas, A. J., Gotlinger, K. H., Hwang, S. H., Hammock, B. D., Schwartzman, M. L., & Huang, A. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00920.2013 · Cited by 33
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“activity (30, 31), Ca(2) /calmodulin (32), and CaMKII (33, 34).”
Background
TIMP-2 modulates VEGFR-2 phosphorylation and enhances phosphodiesterase activity in endothelial cells
Lee, S.-J., Tsang, P. S., Diaz, T., Wei, B., & Stetler‐Stevenson, W. G. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2009.136 · Cited by 33
(-)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT
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“Shear stress can also activate eNOS independently of large and sustained increases in [Ca]i, but this stimulation results in rather low NO production compared with agonist-evoked effects, where large increases in [Ca]i are induced [26].”
Background
CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway1
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Increased caveolae density and caveolin-1 expression accompany impaired NO-mediated vasorelaxation in diet-induced obesity
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“…(and other serine/threonine kinases) which increases caveolin-1 binding and reduces calmodulin binding to eNOS (Bauer et al. 2003; Chen et al. 2008; Fleming et al. 2001; Li et al. 2007), and increased CK2 phosphorylation of calmodulin which attenuates calmodulin activation and displaces calmodulin…”
Background
Spectroscopic characterization of the iron-oxo intermediate in cytochrome P450
Jung, C., Schünemann, V., Lendzian, F., TRAUTWEIN, A. X., Contzen, J., Galander, M., Böttger, L. H., Richter, M., & Barra, A. (2005) · Biological Chemistry · doi:10.1515/bc.2005.120 · Cited by 33
Differential mechanisms of hepatic vascular dysregulation with mild vs. moderate ischemia-reperfusion
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Self-citation
Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats
Jabs, A., Oelze, M. W., Mikhed, Y., Stamm, P., Kröller‐Schön, S., Welschof, P., Jansen, T., Hausding, M., Kopp, M., Steven, S., et al. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.03.007 · Cited by 34
CGRP signalling inhibits NO production through pannexin-1 channel activation in endothelial cells
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Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease
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“PKC may cause phosphorylation of Thr-495 and dephosphorylation of Ser-1175 in eNOS and in turn inhibit NO production [109,110].”
Background
A PP2A‐mediated feedback mechanism controls Ca 2+ ‐dependent NO synthesis under physiological oxygen
Keeley, T. P., Siow, R. C. M., Jacob, R., & Mann, G. E. (2017) · The FASEB Journal · doi:10.1096/fj.201700211r · Cited by 32
Nitric oxide generation mediated by ?-adrenoceptors is impaired in platelets from patients with Type 2 diabetes mellitus
Queen, L. R., Ji, Y. H., Goubareva, I., & Ferro, A. (2003) · Diabetologia · doi:10.1007/s00125-003-1219-0 · Cited by 32
“Phosphorylation of Thr 495 is generally associated with a decrease in enzyme activity [ 41 , 42].”
Background
Pharmacological Efficacy of CPU 86017 on Hypoxic Pulmonary Hypertension in Rats
Zhang, T., Cui, B., Dai, D., & Tang, X. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000184470.58047.79 · Cited by 32
Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.
Li, Z., Carter, J. D., Dailey, L. A., & Huang, Y.-C. T. (2003) · Environmental Health Perspectives · doi:10.1289/ehp.6477 · Cited by 32
“Many agonist stimuli, such as vascular endothelial growth factor (VEGF) (Michell et al. 2001), bradykinin (Fleming et al. 2001; Harris et al. 2001), and ischemic stress (Chen ZP et al. 1999), inhibit phosphorylation at the Thr495 residue.”
BackgroundResult
AT1 receptor blocker potentiates shear-stress induced nitric oxide production via modulation of eNOS phosphorylation of residues Thr495 and Ser1177
Baraúna, V. G., Mantuan, P. R., Magalhães, F. D. C., Campos, L. C. G., & Krieger, J. E. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.10.108 · Cited by 31
Statins in Endothelial Signaling and Activation
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Nongenomic Estrogen Effects on Nitric Oxide Synthase Activity in Rat Adipocytes
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Vascular Endothelial Growth Factor Receptor-2 Activates ADP-ribosylation Factor 1 to Promote Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells
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Insulin Regulates Nitric Oxide Production in the Kidney Collecting Duct Cells
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“We have not directly assessed the activation of these kinases; however, studies done in other cell systems have not shown insulin stimulation of eNOS via calcium/calmodulin-dependent protein kinase II or PKA (47, 48).”
Background
Shenfu Injection Promotes Vasodilation by Enhancing eNOS Activity Through the PI3K/Akt Signaling Pathway In Vitro
Zhu, J., Song, W., Xu, S., Ma, Y., Wei, B., Wang, H., & Hua, S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00121 · Cited by 30
“Phosphorylation at Thr495 reduces the binding of CaM to eNOS, thereby inhibiting the activity of eNOS (Fleming et al., 2001), while phosphorylation at Ser1177 can enhance the catalytic ability of eNOS by inhibiting the separation of CaM from eNOS and enhancing the internal electron transfer rate of…”
Background
Protection of Blood Retinal Barrier and Systemic Vasculature by Insulin-Like Growth Factor Binding Protein-3
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Urocortin II Induces Nitric Oxide Production Through cAMP and Ca2+ Related Pathways in Endothelial Cells
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Role of Protease-Activated Receptor-1 in Endothelial Nitric Oxide Synthase-Thr495 Phosphorylation
Watts, V. L., & Motley, E. D. (2008) · Experimental Biology and Medicine · doi:10.3181/0807-rm-233 · Cited by 30
“Since bradykinin has been shown to induce eNOS-Thr495 phosphorylation via the bradykinin receptor, B1, we used bradykinin as a positive control (10, 11).”
Method
Regulation of red blood cell deformability is independent of red blood cell-nitric oxide synthase under hypoxia
Grau, M., Lauten, A., Hoeppener, S., Goebel, B., Brenig, J., Jung, C., Bloch, W., & Suhr, F. (2016) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-162044 · Cited by 31
Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions
Liang, X., Wang, R., Guo, Y., Cheng, Z., Lv, D., Luo, M., He, A., Luo, S., & Xia, Y. (2021) · FEBS Open Bio · doi:10.1002/2211-5463.13194 · Cited by 29
Gomisin J from Schisandra chinensis induces vascular relaxation via activation of endothelial nitric oxide synthase
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Phosphorylation of Neuronal and Endothelial Nitric Oxide Synthase in the Kidney with High and Low Salt Diets
Mount, P. F., Fraser, S. A., Watanabe, Y., Lane, N., Katsis, F., Chen, Z., Kemp, B. E., & Power, D. A. (2005) · Nephron Physiology · doi:10.1159/000089092 · Cited by 29
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P2Y receptors as regulators of lung endothelial barrier integrity
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“[82,83] NO stimulates guanylate cyclase (GC), resulting in an elevation of second messenger cGMP levels and cGMPdependent protein kinase G (PKG) activation.”
Background
Targeting caveolin-3 for the treatment of diabetic cardiomyopathy
Murfitt, L., Whiteley, G., Iqbal, M. M., & Kitmitto, A. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.03.002 · Cited by 29
“Phosphorylation of Thr495 by PKC is proposed to be inhibitory by preventing calmodulin binding (Fleming et al., 2001).”
Background
Insulin Stimulates Nitric Oxide Production in Rat Adipocytes
Ribière, C., Jaubert, A., Sabourault, D., Lacasa, D., & Giudicelli, Y. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6444 · Cited by 29
Cyclin-Dependent Kinase 5 Phosphorylates Endothelial Nitric Oxide Synthase at Serine 116
Cho, D., Seo, J., Park, J., Jo, C., Choi, Y. J., Soh, J., & Jo, I. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.140210 · Cited by 29
Protein Kinase CβII-Mediated Phosphorylation of Endothelial Nitric Oxide Synthase Threonine 495 Mediates the Endothelial Dysfunction Induced by FK506 (Tacrolimus)
Chiasson, V. L., Quinn, M. A., Young, K. J., & Mitchell, B. M. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.178095 · Cited by 29
“PKC activation is known to decrease NO production, which may be mediated by its direct effects on eNOS phosphorylation sites (Fleming et al., 2001; Matsubara et al., 2003).”
Background
Vascular CaMKII: heart and brain in your arteries
Toussaint, F., Charbel, C., Allen, B. G., & Ledoux, J. (2016) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00341.2015 · Cited by 29
Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease
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“Moreover, PKC has been suggested to regulate eNOS expression and activity in vascular cells, through different isoform activation (Davda et al., 1994; Fleming et al., 2001; Michell et al., 2001).”
Background
Beneficial effect of the oligomerized polyphenol oligonol on high glucose‐induced changes in eNOS phosphorylation and dephosphorylation in endothelial cells
Zhang, X., Yokoo, H., Nishioka, H., Fujii, H., Matsuda, N., Hayashi, T., & Hattori, Y. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00594.x · Cited by 28
“Several lines of evidence have suggested that eNOS is regulated, in part, through the coordinated phosphorylation and dephosphorylation of the amino acid residues Ser-1177 and Thr-495 (Fulton et al., 1999; Fleming et al., 2001; Harris et al., 2001; Michell et al., 2001).”
BackgroundInfluential
2-(2,4-dihydroxyphenyl)-5-(E)-propenylbenzofuran promotes endothelial nitric oxide synthase activity in human endothelial cells
Ladurner, A., Atanasov, A. G., Heiß, E. H., Baumgartner, L., Schwaiger, S., Rollinger, J. M., Stuppner, H., & Dirsch, V. M. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.06.029 · Cited by 28

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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