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

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1161/hh1101.092677

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., & Zeiher, A. M. (1999) · Nature · doi:10.1038/21224 · Cited by 3,591
Self-citation
Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase
Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C. J., Reed, R. R., & Snyder, S. H. (1991) · Nature · doi:10.1038/351714a0 · Cited by 2,354
Dynamic activation of endothelial nitric oxide synthase by Hsp90
García‐Cardeña, G., Fan, R., Shah, V. H., Sorrentino, R., Cirino, G., Papapetropoulos, A., & Sessa, W. C. (1998) · Nature · doi:10.1038/33934 · Cited by 1,029
AMP‐activated protein kinase phosphorylation of endothelial NO synthase
Chen, Z.-P., Mitchelhill, K. I., Michell, B. J., Stapleton, D., Rodríguez‐Crespo, I., Witters, L. A., Power, D. A., de Montellano, P. R. O., & Kemp, B. E. (1999) · FEBS Letters · doi:10.1016/s0014-5793(98)01705-0 · Cited by 839
Self-citation
Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase.
Nishida, K., Harrison, D. G., Navas, J. P., Fisher, A. A., Dockery, S., Uematsu, M., Nerem, R. M., Alexander, R. W., & Murphy, T. J. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116092 · Cited by 735
Endothelial Nitric Oxide Synthase Is Regulated by Tyrosine Phosphorylation and Interacts with Caveolin-1
García‐Cardeña, G., Fan, R., Stern, D. F., Liu, J., & Sessa, W. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27237 · Cited by 533
Phosphorylation of Endothelial Nitric Oxide Synthase in Response to Fluid Shear Stress
Corson, M. A., James, N. L., Latta, S. E., Nerem, R. M., Berk, B. C., & Harrison, D. G. (1996) · Circulation Research · doi:10.1161/01.res.79.5.984 · Cited by 521
Calcium‐dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin
Busse, R., & Mülsch, A. (1990) · FEBS Letters · doi:10.1016/0014-5793(90)80902-u · Cited by 511
Self-citation
Molecular cloning and characterization of human endothelial nitric oxide synthase
Marsden, P. A., Schappert, K. T., Chen, H. S., Flowers, M. A., Sundell, C. L., Wilcox, J. N., Lamas, S., & Michel, T. M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)80697-f · Cited by 489

Show all 38 references

Research works printed but not linked: 5

10.1161/hyp.25.2.180 · DOI
10.1161/res.79.5.984 · DOI
10.1161/res.82.6.686 · DOI
Fulton D, Gratton J-P, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt [published correction appears in Nature. 1999;400:792]. Nature. 1999;399:597–601.
10.1161/res.78.5.750 · DOI

Sorted by citations

Items 601–700 of 770

Clinical Impact and Mechanisms of Nonatherosclerotic Vascular Aging: The New Kid to Be Blocked
Jouabadi, S. M., Ataabadi, E. A., Golshiri, K., Bos, D., Stricker, B. H. C., Danser, A. H. J., Mattace-Raso, F. U. S., & Roks, A. J. M. (2023) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2023.07.022 · Cited by 8
Endothelial regulation of calmodulin expression and eNOS–calmodulin interaction in vascular smooth muscle
Stencel, M. G., VerMeer, M., Giles, J. R., & Tran, Q. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04391-7 · Cited by 7
Transient Insulin Resistance in Normal Subjects: Acute Hyperglycemia Inhibits Endothelial-Dependent Vasodilatation in Normal Subjects
Rammos, G., Peppes, V., & Zakopoulos, N. (2008) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2007.0036 · Cited by 7
Interaction between NO synthase and NADPH oxidase in control of sodium transport by the renal thick ascending limb during diabetes
Miguel, C. D., Foster, J. M., Carmines, P. K., & Pollock, J. S. (2013) · Acta Physiologica · doi:10.1111/apha.12144 · Cited by 7
“PKC has been shown to directly phosphorylate NOS3 constitutively at threonine 495 in endothelial cells, with PKC inhibition associated with an increase in endothelial NO production (Fleming et al. 2001).”
Background
eNOS phosphorylation and translocation are altered in male but not female mice by increased activation of the Gαq protein
Ruiz-Holst, C., Bölck, B., Ghanem, A., Tiemann, K., Brokat, S., Regitz‐Zagrosek, V., Bloch, W., Schwinger, R. H. G., & Brixius, K. (2010) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y09-115 · Cited by 7
Cellular mechanisms and intracellular signaling pathways for the modulation of eNOS in pulmonary arteries by 15-HETE
Yu, L., Liu, Y., Qiu, Z., Liu, S., Gao, X., & Zhu, D. (2012) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2012.660530 · Cited by 7
Phosphorylation of myocardial eNOS is altered in patients suffering from type 2 diabetes
Streit, U., Reuter, H., Bloch, W., Wahlers, T., Schwinger, R. H. G., & Brixius, K. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00011.2011 · Cited by 7
Endothelial modulation of a nitric oxide donor complex-induced relaxation in normotensive and spontaneously hypertensive rats
Potje, S. R., Troiano, J. A., Grando, M. D., Graton, M. E., da Silva, R. S., Bendhack, L. M., & Antoniali, C. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.03.055 · Cited by 7
Mitochondrial depolarization stimulates vascular repair‐relevant functions of CD34+ cells via reactive oxygen species‐induced nitric oxide generation
Joshi, S., & Jarajapu, Y. P. R. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14529 · Cited by 7
“This suggests that the dephosphorylation of eNOS-Thr(495) is sufficient for the functional generation of NO, as shown previously in several other studies (Fleming et al., 2001; Harris et al., 2001; Michell et al., 2001).”
Result
Docosahexaenoic acid reduces adenosine triphosphate-induced calcium influx via inhibition of store-operated calcium channels and enhances baseline endothelial nitric oxide synthase phosphorylation in human endothelial cells
Vu, T. T., Dieterich, P., Vu, T. T., & Deußen, A. (2019) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2019.23.5.345 · Cited by 7
“Because eNOS is activated when phosphorylated at residue ser1177 and in-activated when phosphorylated at residue thr495 [17] we tested the impact of ATP and DHA on eNOS phosphorylation.”
Background
Effects of S-nitrosation of nitric oxide synthase
(2007) · Advances in experimental biology · doi:10.1016/s1872-2423(07)01007-1 · Cited by 7
Inhibition of cardiac cytochrome P450: a new approach to cardiac ischaemia and reperfusion damage
Doggrell, S. A. (2004) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.8.5.491 · Cited by 7
Molecular Cloning of Ovine Endothelial Nitric Oxide Synthase and Expression in COS-7 Cells
Cale, J. M., Tsoi, S. C. ‐., Toppe, M., Grummer, M. A., Ochiai, M., Magness, R. R., & Bird, I. M. (2005) · Journal of the Society for Gynecologic Investigation · doi:10.1016/j.jsgi.2004.11.006 · Cited by 7
Redox Regulation of Dihydrofolate Reductase
Münzel, T. F., & Daiber, A. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.306556 · Cited by 7
Quantitative determination of urinary trichloroacetic acid as an index of trichloroethylene exposure by high performance liquid chromatography.
Ogata, M., & YAMAZAKI, Y. (1979) · PubMed · doi:10.18926/amo/32049 · Cited by 7
Telmisartan-induced eNOS gene expression is partially independent of its PPAR-gamma agonist property
Buset-Ríos, N., Rodríguez‐Esparragón, F., & Pérez, J. C. R. (2012) · Clinical and investigative medicine · doi:10.25011/cim.v35i2.16289 · Cited by 6
Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation
Subramanian, K., Naik, V. D., Sathishkumar, K., Sawant, O. B., Washburn, S. E., Wu, G., Yallampalli, C., Saade, G. R., Hankins, G. D. V., & Ramadoss, J. (2013) · Reproductive Toxicology · doi:10.1016/j.reprotox.2013.11.006 · Cited by 6
Novel Pathophysiological Mechanisms in Hypertension
Samson, R., Lee, A., Lawless, S. M., Hsu, R. C., & Sander, G. E. (2016) · Advances in experimental medicine and biology · doi:10.1007/5584_2016_96 · Cited by 6
Subcellular Targeting of Nitric Oxide Synthases Mediated by Their N-Terminal Motifs
Costas‐Insua, C., Merino, J., Aicart-Ramos, C., & Rodríguez‐Crespo, I. (2017) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2017.07.002 · Cited by 5
Shear Stress and RBC-NOS Serine1177 Phosphorylation in Humans: A Dose Response
Horobin, J. T., Sabapathy, S., Kuck, L., & Simmonds, M. J. (2021) · Life · doi:10.3390/life11010036 · Cited by 6
The role of phosphorylation in atrial fibrillation: a focus on mass spectrometry approaches
Safabakhsh, S., Panwar, P., Barichello, S., Sangha, S. S., Hanson, P., Petegem, F. V., & Laksman, Z. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab095 · Cited by 7
Compound 48/80 induces endothelium-dependent and histamine release-independent relaxation in rabbit aorta
Viaro, F., Celotto, A. C., Capellini, V. K., Baldo, C. F., Rodrigues, A. J., Vicente, W. V. D. A., & Évora, P. R. B. (2007) · Nitric Oxide · doi:10.1016/j.niox.2007.11.004 · Cited by 6
“For example, agonist induced activation of the calmodulin-dependent protein kinase II is highly dependent on an increase in intracellular calcium concentration, whereas the shear stress induced activation of protein kinase B (PKB) is not affected by calcium removal [22,23].”
Background
Efectos del óxido nítrico sobre la función cardíaca
Tamargo, J. L., Caballero, R., Gómez, R. J., Núñez, L., Vaquero, M., & Delpón, E. (2006) · Revista Española de Cardiología Suplementos · doi:10.1016/s1131-3587(06)74816-6 · Cited by 6
Traditional Chinese medicine’s intervention in endothelial nitric oxide synthase activation and nitric oxide synthesis in cardiovascular system
Zhu, J., Song, W., Hu, Z., Ye, Q.-F., Liang, Y., & Kang, L. (2015) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-015-1964-1 · Cited by 6
Relaxation induced by the nitric oxide donor and cyclooxygenase inhibitor NCX2121 in renal hypertensive rat aortas
de Paula, T. D., Silva, B. R., Grando, M. D., Pernomian, L., do Prado, A. F., & Bendhack, L. M. (2017) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2017.06.007 · Cited by 6
“As described by Fleming et al. (2001) eNOS is activated in the endothelial cells by calcium transient, that is increased by Ser1177 phosphorylation and dephosphorylation at Thr495.”
Background
Omeprazole suppresses endothelial calcium response and eNOS Ser1177 phosphorylation in porcine aortic endothelial cells
Kamiya, C., Odagiri, K., Hakamata, A., Sakurada, R., Inui, N., & Watanabe, H. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06561-0 · Cited by 6
Dipeptidyl peptidase 4 inhibitor reduces intimal hyperplasia in rabbit autologous jugular vein graft under poor distal runoff
Kôyama, A., Komori, K., Otsuka, R., Kajikuri, J., & Itoh, T. (2015) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2014.12.048 · Cited by 6
The Basal Phosphorylation Sites of Endothelial Nitric Oxide Synthase at Serine (Ser)1177, Ser116, and Threonine (Thr)495 in Rat Molar Epithelial Rests of Malassez
Korkmaz, Y., Bloch, W., Addicks, K., Schneider, K., Baumann, M. A., & Raab, W. H.-M. (2005) · Journal of Periodontology · doi:10.1902/jop.2005.76.9.1513 · Cited by 6
Characterization of agonist‐induced endothelium‐dependent vasodilatory responses in the vascular bed of the equine digit
Berhane, Y., BAILEY, S. R., Putignano, C., & Elliott, J. (2007) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/j.1365-2885.2007.00912.x · Cited by 6
Biology of Nitric Oxide Synthases
Fleming, I. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-374530-9.00003-6 · Cited by 6
Self-citation
Piezo1 activates nitric oxide synthase in red blood cells via protein kinase C with increased activity in diabetes
Sangha, G. S., Smith, L. V., Kheradmand, M., Munir, K. M., Rangachar, N., Weber, C. M., Safari, Z., Rogers, S. C., Doctor, A., & Clyne, A. M. (2025) · Mechanobiology in Medicine · doi:10.1016/j.mbm.2025.100145 · Cited by 5
“23,24 Given their shared mechanotransduction pathways, it is currently thought that both cell types activate eNOS in response to shear stress through Akt-mediated signaling pathways.”
The lncRNA DSCR9 is modulated in pulmonary arterial hypertension endothelial cell models and is associated with alterations in the nitric oxide pathway
Bernardi, N., Neep, B., Garibaldi, S., Bianconi, E., Aman, J., Valldeperas, A. L., Sirello, D., Zoppoli, G. M., de Man, F. S., & Ameri, P. (2025) · Vascular Pharmacology · doi:10.1016/j.vph.2025.107464 · Cited by 5
Microvascular Consequences of Obesity and Diabetes
Bohlen, H. G. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-374530-9.00021-8 · Cited by 5
Extract of Rubus coreanus Fruits Increases Expression and Activity of Endothelial Nitric Oxide Synthase in the Human Umbilical Vein Endothelial Cells
Yoon, H. J., Park, S. Y., Oh, S.-T., Lee, K.-Y., & Yang, S.-Y. (2011) · Journal of Life Science · doi:10.5352/jls.2011.21.1.44 · Cited by 5
“Phosphorylation of Ser116 and Thr495 negatively regulates eNOS activity, whereas phosphorylation of Ser635 and Ser1177 has the opposite effect of increasing eNOS activity [11,15,40].”
Background
Thrombin induces a temporal biphasic vascular response through the differential phosphorylation of endothelial nitric oxide synthase via protease-activated receptor-1 and protein kinase C
Okamura, A., Miake, J., Tomomori, T., Takami, A., Sawano, T., Kato, M., Ogura, K., Tsujimoto, D., Kawatani, S., Priyono, A. K., et al. (2022) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2022.02.001 · Cited by 5
Akt and Ca2+ signaling in endothelial cells
Ozeki, M., Watanabe, H., Luo, J., Nakano, T., Takeuchi, K., Kureishi, Y., Ito, M., Nakano, T., Ohashi, K., & Hayashi, H. (2004) · Molecular and Cellular Biochemistry · doi:10.1023/b:mcbi.0000021369.17958.f4 · Cited by 5
“This is consistent with previous findings that Akt is basally phosphorylated and active in unstimulated PAECs [ 35 ].”
Result
Programación epigenética placentaria en restricción del crecimiento intrauterino
Casanello, P. C., Castro-Rodríguez, J. A., Uauy, R. D., & Krause, B. J. (2016) · Revista chilena de pediatría · doi:10.1016/j.rchipe.2016.04.009 · Cited by 6
Zur Funktion des β3-Adrenozeptors am Herzen: Signaltransduktion, inotroper Effekt und therapeutischer Ausblick
Pott, C., Steinritz, D., Napp, A., Bloch, W., Schwinger, R. H. G., & Brixius, K. (2006) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-006-0273-x · Cited by 5
Overexpressed p32 localized in the endoplasmic reticulum and mitochondria negatively regulates calcium‑dependent endothelial nitric oxide synthase activit
Choi, K., Koo, B., Yoon, B., Jung, M., Yun, H., Jeon, B., Won, M., Kim, Y., Mun, J., Lim, H. K., et al. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11307 · Cited by 5
Amorphous nanosilica particles evoke vascular relaxation through PI 3K/Akt/ eNOS signaling
Onodera, A., Yayama, K., Tanaka, A., Morosawa, H., Furuta, T., Takeda, N., Kakiguchi, K., Yonemura, S., Yanagihara, I., Tsutsumi, Y. M., et al. (2016) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12206 · Cited by 6
Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ.
Li, M., Tejada, T., Lambert, J. P., Nicholson, C. K., Yahiro, E., Ambai, V. T., Ali, S. F., Bradley, E. W., Graham, R. M., Dell’Italia, L. J., et al. (2016) · PubMed Central · Cited by 5
Investigation of the structure and dynamic of calmodulin-nitric oxide synthase complexes using NMR spectroscopy
Guillemette, J. G. (2018) · Frontiers in bioscience · doi:10.2741/4680 · Cited by 5
“For example, phosphorylation of S1177 in the reductase domain has been found to result in the activation of eNOS, whereas the phosphorylation of T495 within the CaM-binding domain has been found to act as a negative regulatory site reducing eNOS activity (91–93).”
Background
Critical Regulators of Endothelial Cell Functions: For a Change Being Alternative
Farrokh, S., Brillen, A.-L., Haendeler, J., Altschmied, J., & Schaal, H. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6023 · Cited by 6
The developmental stage and cell type dependent phosphorylation of eNOS in murine enteric mucosa and myenteric plexus
Korkmaz, H., Bloch, W., Bölck, B., Labbé, D., Addicks, K., & Arnhold, S. (2007) · Journal of Molecular Histology · doi:10.1007/s10735-007-9091-8 · Cited by 5
“In endothelial cells, the activity of eNOS is increased by phosphorylation of the enzyme at Ser(1177) (human amino acid residue) and at Ser(635) (bovine amino acid) and decreased by phosphorylation at Thr(495) (human amino acid) and Ser(116) (bovine amino acids) (Michell et al. 2001; Harris et al. 2001; Fleming et al.…”
BackgroundInfluential
Double Tribble
Fleming, I. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.169250 · Cited by 5
Self-citation
Endothelial nitric oxide synthase phosphorylated at Ser116 is localized in nerve fibers of the rat glandulae palatinae
Korkmaz, Y., Bloch, W., Addicks, K., Baumann, M. A., & Raab, W. H.-M. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.03.045 · Cited by 5
Circulating endothelial extracellular vesicles progressively increase with age and are associated with endothelial vasodilator dysfunction
DeSouza, C. S., Stockelman, K. A., Hijmans, J. G., Bammert, T. D., Lincenburg, G. M., Greiner, J. J., Garcia, V. P., Stauffer, B. L., & DeSouza, C. A. (2025) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00146.2025 · Cited by 4
NO-cGMP Signaling in Endothelial Function of the Healthy and Inflamed Dental Pulp
Korkmaz, Y., Kollmar, T., Schultheis, J. F., Ziskoven, P. C., Müller-Heupt, L. K., & Deschner, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010057 · Cited by 4
The machinery of healthy vasodilatation: an overview
Pourová, J., Dias, P., Pour, M., & Mladěnka, P. (2025) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-025-03096-2 · Cited by 4
B56δ subunit of protein phosphatase 2A decreases phosphorylation of endothelial nitric oxide synthase at serine 116: Mechanism underlying aphidicolin-stimulated NO production
Park, J., Cho, D., Lee, J. Y., Lee, H.-J., Ha, Y.-N., Ahn, J., & Jo, I. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.08.001 · Cited by 4
Nitric Oxide Production and its Contribution to Hepatocyte Proliferation in Normal Juvenile Rats
INUKAI, N., UCHIDA, M., Miyazaki, Y., Suzuki, T., Yoshikawa, H., Tanaka, K., Morita, H., & Takizawa, T. (2010) · Journal of Veterinary Medical Science · doi:10.1292/jvms.09-0551 · Cited by 4
Role of Protein Kinase C and Related Pathways in Vascular Smooth Muscle Contraction and Hypertension
Qiao, X., & Khalil, R. A. (2009) · doi:10.1093/acprof:oso/9780195326697.003.0002 · Cited by 4
Targeting the NO-sGC-cGMP Pathway in Pulmonary Arterial Hypertension
Watanabe, H., & Tran, Q. (2017) · Springer eBooks · doi:10.1007/978-981-287-840-3_11 · Cited by 4
Endothelium: Dysfunction and Repair
Ozkor, M. A., Murrow, J. R., & Quyyumi, A. A. (2009) · Springer eBooks · doi:10.1007/978-1-84882-637-3_11 · Cited by 4
Enhancement of Nitric Oxide Production Is Responsible for Minimal Intimal Hyperplasia of Autogenous Rabbit Arterial Grafts
Tabata, K., Komori, K., Otsuka, R., Kajikuri, J., & Itoh, T. (2017) · Circulation Journal · doi:10.1253/circj.cj-17-0034 · Cited by 4
Dephosphorylation of eNOS on Thr495 after transient forebrain ischemia in gerbil hippocampus
Hashiguchi, A., Yano, S., Morioka, M., Hamada, J., Kochi, M., & Fukunaga, K. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.10.042 · Cited by 4
The mechanism of VEGF-mediated endothelial cells survival and proliferation in conditions of unfed-culture
Nikolaienko, T. V., Nikulina, V. V., Шелест, Д. В., & Garmanchuk, L. (2016) · The Ukrainian Biochemical Journal · doi:10.15407/ubj88.04.012 · Cited by 4
Diabetes mellitus and endothelial dysfunction: a central role for oxidative stress
Schulz, E., & Keaney, J. F. (2003) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/00060793-200308000-00002 · Cited by 4
ATVB In Focus
Cohen, R. A. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000137187.16206.79 · Cited by 4
Mucopolysaccharide polysulfate increases local skin blood volume through nitric oxide production
Kurachi, T., Ishimaru, H., Tadakuma, R., Okaue, M., Koda, A., Ueda, Y., & Doi, T. (2024) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2024.05.001 · Cited by 3
A preclinical randomised controlled dose optimization of megadose sodium ascorbate for reversal of gram-negative sepsis-induced cardiovascular, brain and kidney dysfunction
Ow, C. P. C., Peiris, R. M., Trask-Marino, A. L., Hood, S. G., Betrie, A. H., Lane, D. J. R., Bellomo, R., Plummer, M. P., May, C. N., & Lankadeva, Y. R. (2025) · Critical Care · doi:10.1186/s13054-025-05799-5 · Cited by 3
Protocatechuic Acid, a Gut-Derived Dietary Metabolite, Attenuates Endothelial Dysfunction via GPER-Mediated NO Signaling
Lee, S. Y., Kim, J. W., Bui, A. T. N., Maeng, J., Lee, G. H., Jo, W., Lee, S. K., Yun, H.-Y., Han, E. H., & Jeong, H. (2026) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c15753 · Cited by 3
Molecular mechanisms of exercise-induced cardiac rehabilitation
Ren, H., Jiang, C., Luo, Y., Liang, F., Nie, Z., Zhuo, P., Ke, X., & Wen, Y. (2026) · Life Sciences · doi:10.1016/j.lfs.2026.124476 · Cited by 5
Klebsiella pneumoniae inhibits vasodilation through capsule and T6SS-dependent pathways
Rehman, S., Sá‐Pessoa, J., Buckley, C., Lee, R. L., Wojtania, K., Lee, A., Lancaster, R., Augustine, J., Barabás, P., Ross, C., et al. (2026) · Nature Microbiology · doi:10.1038/s41564-026-02425-0 · Cited by 5
Nutrient regulation of inflammatory signalling in obesity and vascular disease
Palmer, T. M., & Salt, I. P. (2021) · Clinical Science · doi:10.1042/cs20190768 · Cited by 3
CURRENT APPROACHES TO THE IDENTIFICATION OF CELLULAR MARKERS OF ENDOTHELIAL DYSFUNCTION
Bogdanov, L. A., Koshelev, V. A., Mukhamadiyarov, R. А., Kanonykina, A., Lazebnaya, A. A., Андреевич, К. Е., Stepanov, A. D., & Kutikhin, A. G. (2024) · Complex Issues of Cardiovascular Diseases · doi:10.17802/2306-1278-2024-13-3s-191-207 · Cited by 3
Reduced Function of Endothelial Nitric Oxide and Hyperpolarization in Artery Grafts with Poor Runoff
Sakakibara, M., Kodama, A., Komori, K., & Itoh, T. (2021) · Journal of Surgical Research · doi:10.1016/j.jss.2021.08.031 · Cited by 3
Cardioprotection by poloxamer 188 is mediated through increased endothelial nitric oxide production
Chen, G., Douglas, H. F., Li, Z., Cleveland, W. J., Balzer, C., Yannopoulos, D., Chen, I. Y., Obal, D., & Riess, M. L. (2025) · Scientific Reports · doi:10.1038/s41598-025-97079-z · Cited by 3
Vascular Endothelial Dysfunction and Atherosclerosis: Role of Nitric Oxide System
Simo‐Cheyou, E. R., & Srivastava, A. K. (2015) · Springer eBooks · doi:10.1007/978-3-319-15961-4_26 · Cited by 4
“By maintaining a sustained phosphorylation of eNOS on Thr 495/497 , PKC-β antagonises agonist-induced eNOS activation and subsequent NO release [ 105 , 106 ].”
Background
Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation
Ulke‐Lemée, A., Sun, D., Ishida, H., Vogel, H. J., & MacDonald, J. A. (2017) · BMC Biochemistry · doi:10.1186/s12858-017-0080-6 · Cited by 3
NO Signaling Defects in Hypertension
Fleming, I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00023-5 · Cited by 3
Self-citation
COMPARISON OF MODIFIED ENDOTHELIAL NITRIC OXIDE SYNTHASE FORMS IN HYPERTENSIVE AND NORMOTENSIVE RATS
Bogdanov, L. A., Kondratiev, E. A., Koshelev, V. A., Mukhamadiyarov, R. А., Kanonykina, A., Lazebnaya, A. A., Евгеньевна, Т. А., & Кутихин, А. Г. (2025) · Complex Issues of Cardiovascular Diseases · doi:10.17802/2306-1278-2025-14-2-110-126 · Cited by 2
Resveratrol Improves Endothelial Function by A PREP1-Mediated Pathway in Mouse Aortic Endothelial Cells
Cabaro, S., Agognon, A. L., Nigro, C., Orso, S., Prevenzano, I., Leone, A., Morelli, M. C., Mormone, F., Romano, S., Miele, C., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511891 · Cited by 2
“Although we cannot exclude the involvement of other PKCs on eNOSthr495 phosphorylation, previous studies that were performed using activators or inhibitors of the classical PKC have driven our focus toward PKCα isoform [7,8].”
Result
Human Pulmonary Artery Endothelial Cells Increased Glycolysis and Decreased Nitric Oxide Synthase O-GlcNAcylation in Pulmonary Arterial Hypertension
Basehore, S. E., & Clyne, A. M. (2024) · International Journal of Translational Medicine · doi:10.3390/ijtm4010007 · Cited by 2
“…glycolytic intermediates These data suggest that relative glucose flux in glycolysis did not change in PAH HPAECs, but rather that increased glucose uptake contributed to higher glycolytic intermediates in PAH HPAECs. in PAH HPAECs. each condition omi tt ed. ns: not signi ﬁ cant; ** p < 0.001.”
Influential
Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs
Liang, Z., Sun, G., Zhang, J., Zhang, Q., Li, X., Qin, S., Lv, S., Ding, J., Zhang, Q., Xia, Y., et al. (2024) · Experimental Cell Research · doi:10.1016/j.yexcr.2024.113998 · Cited by 3
Role of Oxygen-Derived Species in the Regulation of Pulmonary Vascular Tone
Wolin, M. S., Ahmad, M., & Gupte, S. A. (2010) · Springer eBooks · doi:10.1007/978-0-387-87429-6_18 · Cited by 2
Chapter 1 Approaches for Studying Angiogenesis‐Related Signal Transduction
Derakhshan, B., Harrison, K. D., Miao, Q., & Sessa, W. C. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)02001-6 · Cited by 2
“This increase in intracellular calcium also activates Cam kinase II (CaMKII), which also serves to phosphorylate Ser1179 of eNOS and increase NO production (Fleming et al., 2001).”
Harboring of NOS to the Cell Membrane
Rőszer, T. (2012) · Springer eBooks · doi:10.1007/978-94-007-2819-6_6 · Cited by 2
The Peroxisome Proliferator-Activated Receptor δ Agonist, GW501516, Inhibits Angiogenesis through Dephosphorylation of Endothelial Nitric Oxide Synthase
Kim, J.-B., Lee, S. H., Ahn, J., & Kim, J. (2012) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2012.1.1.11 · Cited by 2
Structural and Functional Characteristics of a Soluble Form of Endoglin in the Context of Preeclampsia
Gregory, A. (2011) · TSpace (University of Toronto) · Cited by 2
Microcirculatory Exchange Function
Durán, W. N., Sánchez, F. A., & Breslin, J. W. (2008) · Comprehensive physiology · doi:10.1002/cphy.cp020404 · Cited by 2
Microvascular Consequences of Obesity and Diabetes
Bohlen, H. G. (2008) · Comprehensive physiology · doi:10.1002/cphy.cp020419 · Cited by 2
Klebsiella pneumoniae disrupts vasodilation by targeting eNOS post translational modifications via the type VI secretion system and the capsule polysaccharidePreprint
Rehman, S., Sá‐Pessoa, J., Buckley, C., Lancaster, R., Ross, C., Zhang, X., McCarron, J. G., Curtis, T. M., & Bengoechea, J. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.05.636584 · Cited by 2
The Role of eNOS in Vascular Diseases
Kuroedov, A., Cosentino, F., Tanner, F. C., & Lüscher, T. F. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-001-0_14 · Cited by 2
Blood Vessels
Sampaio, W. O., & Touyz, R. M. (2019) · Springer eBooks · doi:10.1007/978-3-030-22696-1_7 · Cited by 1
Microcirculatory Exchange Physiology and Molecular Mechanisms Controlling Microvascular Permeability
Breslin, J. W., Motawe, Z. Y., & Chang, M. (2025) · Physiology in health and disease · doi:10.1007/978-3-031-99609-2_2 · Cited by 1
Glutamine Substitution at Lysine 609 in the Autoinhibitory Region Modulates Catalysis, Uncoupling, and Conformational Dynamics of Endothelial Nitric Oxide Synthase
Masood, M., Khan, S., Yameen, D., Anwar, A., Khan, F., Iqbal, S., Chaturvedi, R., Shamsi, A., & Haque, M. M. (2025) · ACS Omega · doi:10.1021/acsomega.5c09928 · Cited by 1
Post-translational regulation of eNOS activity in inflammation
Desjardins, F., & Gratton, J. (2010) · Springer eBooks · doi:10.1007/978-3-0346-0168-9_4 · Cited by 1
“CaM [ 63 ]. Recently, it has been proposed that this site could also act as an intrinsic switch, determining the generation of NO versus superoxide [71].”
BackgroundInfluential
Pharmacology of Nitrovasodilators
Münzel, T. F., & Daiber, A. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_15 · Cited by 1
Molecular dynamics study of in silico mutations in the auto-inhibitory loop of human endothelial nitric oxide synthase FMN sub-domain
Preethi, D., Anishetty, S., & Pennathur, G. (2021) · Journal of Molecular Modeling · doi:10.1007/s00894-020-04643-7 · Cited by 1
Why is early-onset atrial fibrillation uncommon in patients with Duchenne muscular dystrophy? Insights from the mdx mouse
Nguyen, M., Hooper, C. L., Stefanini, M., Vrellaku, B., Carnicer, R., Wood, M. J. A., Simon, J. N., & Casadei, B. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae022 · Cited by 1
Roxadustat Has Beneficial Effects on the Vascular Tone of the Rat Thoracic Aorta
Nakagawa, K., Oshiba, Y., Sukita, R., Hosomi, A., Tawa, M., & Ohkita, M. (2025) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001697 · Cited by 1
Novel roles of thrombospondin-1 in vascular physiology and disease
Bauer, E. M. (2010) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 1
Androgens and Vascular Function
Ferrer, M. (2011) · InTech eBooks · doi:10.5772/18603 · Cited by 1
“…regulatory mechanisms other than PKC could be working on eNOS, including different redox conditions (Polytarchou & Papadimitriou, 2005), phosphatases activity (Fleming et al., 2001) and/or other kinases (Ferrer et al., 2004) that, in their turn, regulate the intracellular environment and function.”
Background
Fasudil (a Rho Kinase Inhibitor) Specifically Increases Cerebral Blood Flow in Area of Vasospasm After Subarachnoid Hemorrhage
Shibuya, M., Meda, K., & Ike, A. (2012) · InTech eBooks · doi:10.5772/34012 · Cited by 1
Mas Receptor
Santos, R. A. S., & Sampaio, W. O. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-801364-9.00027-4 · Cited by 1
Dietary Isoflavones: Cardiovascular Actions and Activation of Cellular Signaling Pathways
Siow, R. C. M., & Mann, G. E. (2009) · Wiley eBooks · doi:10.1002/9780470531792.ch12 · Cited by 1
Estudo da função em artérias de resistência de ratos pós-infarto do miocárdio.
Couto, G. K. (2012) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2012.tde-25072012-095638 · Cited by 1
Activity of endothelial nitric oxide synthase: substrates, modulators and products
Bevers, L. M. (2006) · Utrecht University Repository (Utrecht University) · Cited by 1
Myocardial effect of Intermedin in hypertrophic heart: mechanisms and involvement of endothelial dysfunction
Andreia, M. (2014) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · doi:10.34626/47t6-7a17 · Cited by 1

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks