The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Enhanced Electron Flux and Reduced Calmodulin Dissociation May Explain “Calcium-independent” eNOS Activation by Phosphorylation
Open accessAbstract
Bovine endothelial nitric oxide synthase (eNOS) is phosphorylated directly by the protein kinase Akt at serine 1179. Mutation of this residue to the negatively charged aspartate (S1179D eNOS) increases nitric oxide (NO) production constitutively, in the absence of agonist challenge. Here, we examine the potential mechanism of how aspartate at 1179 increases eNOS activity using purified proteins. Examination of NO production and cytochrome c reduction resulted in no substantial changes in the K(m)/EC(50) for L-arginine, calmodulin, and calcium, whereas there was a 2-fold increase in the rate of NO production for S1179D and a 2-4-fold increase in reductase activity (based on cytochrome c reduction). The observed increase in activity for both assays of NOS function indicates that a faster rate of electron flux through the reductase domain is likely the rate-limiting step in NO formation from eNOS. In addition, S1179D eNOS did show an increased resistance to inactivation by EGTA compared with wild type eNOS. These results suggest that a negative charge imposed at serine 1179, either by phosphorylation or by replacement with aspartate, increases eNOS catalytic activity by increasing electron flux at the reductase domain and by reducing calmodulin dissociation from activated eNOS when calcium levels are low.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
In the citing paper
“NOX1 expression is activated by several factors including angiotensin II, PDGF, and thrombin (382, 492, 630, 695, 999).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [630]
In the citing paper
“Altogether, the role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models (345, 380, 630, 854).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [630]
In the citing paper
“NOX1 deletion limits the blood pressure increase elicited by angiotensin II, although it is unclear if basal blood pressure levels are reduced (345, 346, 630).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [630]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme.
Bredt, D. S., & Snyder, S. H. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.2.682 · Cited by 3,308
Regulation of endothelium-derived nitric oxide production by the protein kinase Akt
Fulton, D. J., Gratton, J., McCabe, T. J. D., Fontana, J. T., Fujio, Y., Walsh, K. X., Franke, T. F., Papapetropoulos, A., & Sessa, W. C. (1999) · Nature · doi:10.1038/21218 · Cited by 2,585
Self-citationPapapetropoulos, A., García‐Cardeña, G., Madri, J. A., & Sessa, W. C. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119868 · Cited by 1,194
Self-citationDynamic 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
Self-citationMammalian nitric oxide synthases
Stuehr, D. J. (1999) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(99)00016-x · Cited by 996
Pollock, J. S., Förstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M., & Murad, F. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.23.10480 · Cited by 979
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
Molecular and Structural Basis of Target Recognition by Calmodulin
Crivici, A., & Ikura, M. (1995) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.bb.24.060195.000505 · Cited by 765
Zeng, G., & Quon, M. J. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118871 · Cited by 726
Cited by
Sorted by citations
Items 201–300 of 385
Disentangling the molecular mechanisms of action of endogenous and environmental estrogens
Nadal, Á., Alonso‐Magdalena, P., Ripoll, C., & Fuentes, E. (2004) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-004-1343-9 · Cited by 35
“The serine/ threonine phosphorylation kinase Akt results in eNOS becoming more active at low [Ca] [47].”
BackgroundJung, S.-B., Kwon, S. K., Kwon, M., Nagar, H., Jeon, B. H., Irani, K., Yoon, S. H., & Kim, C. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.06.049 · Cited by 36
“Many stimulators, including shear stress and DHA, regulate NO production through the phosphorylation of eNOS [5,9] at ser1177 and thr495 [10,11].”
BackgroundEndothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase
Ramadoss, J., Pastore, M. B., & Magness, R. R. (2013) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12136 · Cited by 34
“CaM, Ca calmodulin; Hsp90, heat shock protein 90.(21,23,50) “translocation events occur with activation of eNOS””
BackgroundNitric Oxide and Hormones In Breast Cancer: Allies Or Enemies?
Pance, A. (2006) · Future Oncology · doi:10.2217/14796694.2.2.275 · Cited by 34
“Phosphorylation at this site increases electron flow through the reductase domain, increasing NO production [102].”
BackgroundHendrickson, H. I., Chatterjee, S., Cao, S., Morales‐Ruiz, M., Sessa, W. C., & Shah, V. H. (2003) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00143.2003 · Cited by 34
Self-citationChen, P., & Wu, K. K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305469200 · Cited by 33
Roman, L. J., McLain, J., & Masters, B. S. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212309200 · Cited by 33
Self-citationSu, Y., Qadri, S. M., Wu, L., & Liu, L. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-134 · Cited by 33
“production [53].”
(-)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT
Ramírez‐Sánchez, I., Aguilar, H., Ceballos, G. M., & Villarreal, F. J. (2012) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-012-1405-9 · Cited by 33
“For instance, the phosphorylation of eNOS-Ser1177, Ser633, and Ser615 (human sequence) is associated with increases in enzymatic activity [17, 18], while the phosphorylation of Thr495 is related with eNOS inactivation [19, 20].”
BackgroundTargeting the pentose phosphate pathway in syndrome X‐related cardiovascular complications
Gupte, S. A. (2010) · Drug Development Research · doi:10.1002/ddr.20359 · Cited by 32
Tran, Q., Leonard, J., Black, D. J., & Persechini, A. (2008) · Biochemistry · doi:10.1021/bi8003186 · Cited by 32
“It has been reported that the EC50(Ca) value for CaM-dependent enzyme activation is not affected by this phosphomimetic mutation, although reversal of CaMdependent enzyme activation after addition of a Ca2+ chelator was found to be a slower process with the mutant protein than with the wild-type enzyme (22).”
BackgroundNew fundamental and applied mechanisms in exercise hemorheology
Connes, P., Suhr, F., Martin, C., Shin, S., Aufradet, É., Sunoo, S., Brixius, K., de Mauverger, É. R., Romana, M., Messonnier, L. A., et al. (2010) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-2010-1291 · Cited by 30
“The phosphorylation at Ser1177 is known to increase NO generation [39].”
BackgroundThe influence of the dietary exposome on oxidative stress in pregnancy complications
Prins, J. R., Schoots, M. H., Wessels, J. I., Campmans-Kuijpers, M. J. E., Navis, G. J., van Goor, H., Robertson, S. A., van der Beek, E. M., Sobrevía, L., & Gordijn, S. J. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101098 · Cited by 31
Ko, S., Jung, W., Kang, S., Lee, S., Kang, M. C., Heo, S., Kang, K., Kim, Y.-T., Park, S., Jeong, Y., et al. (2015) · Journal of Functional Foods · doi:10.1016/j.jff.2015.07.003 · Cited by 31
Nongenomic Estrogen Effects on Nitric Oxide Synthase Activity in Rat Adipocytes
Jaubert, A., Mehebik‐Mojaat, N., Lacasa, D., Sabourault, D., Giudicelli, Y., & Ribière, C. (2007) · Endocrinology · doi:10.1210/en.2006-1329 · Cited by 32
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
Horinouchi, T., & Miwa, S. (2021) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2021.07.005 · Cited by 30
Mogami, K., Kishi, H., & Kobayashi, S. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.100 · Cited by 29
Li, Z., Gu, M., Zaparte, A., Fu, X., Mahen, K. K., Mrdjen, M., Li, X. S., Yang, Z., Ma, J., Thoudam, T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-55084-2 · Cited by 34
Casin, K. M., & Kohr, M. J. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101441 · Cited by 27
“Modification of these sites facilitates electron flow through the oxidase and reductase domains that yields an increase in L-arginine reduction, thus altering NO output [47].”
BackgroundAlpha1-adrenergic-mediated eNOS phosphorylation in intact arteries
Looft‐Wilson, R. C., Todd, S. E., Araj, C. A., Mutchler, S. M., & Goodell, C. R. (2012) · Vascular Pharmacology · doi:10.1016/j.vph.2012.09.003 · Cited by 27
“For example, it may increase the sensitization to intracellular calcium as shown in cultured endothelial cells (McCabe et al., 2000).”
BackgroundSedoris, K. C., Ovechkin, A. V., Gozal, E., & Roberts, A. M. (2009) · Archives of Physiology and Biochemistry · doi:10.1080/13813450902785267 · Cited by 27
“While promoting Akt-mediated phosphorylation on eNOS Ser 1177, Hsp90 also improves eNOS activity by increasing eNOS affinity with calmodulin (Takahashi & Mendelsohn, 2003; McCabe et al., 2000), and by promoting dephosphorylation on eNOS threonine 495 (Thr 495) (Kone, 2000).”
BackgroundMathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling
Wu, Q., & Finley, S. D. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051255 · Cited by 26
“dissociation of CaM from eNOS and increases the eNOS catalytic activity [119].”
BackgroundEnhancement of vascular relaxation in rat aorta by phytoestrogens from Curcuma comosa Roxb
Intapad, S., Suksamrarn, A., & Piyachaturawat, P. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.07.005 · Cited by 25
The Mechanisms of L-Arginine Metabolism Disorder in Endothelial Cells
Mammedova, J. T., Av, S., Is, F., & Старикова, Э. А. (2021) · Biochemistry (Moscow) · doi:10.1134/s0006297921020036 · Cited by 26
Xie, L., Talukder, M. A. H., Sun, J., Varadharaj, S., & Zweier, J. L. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.06.015 · Cited by 25
“The functional consequences of eNOS Ser1177 phosphorylation have been studied in detail [48, 49], and this modification confers greater eNOS activation at low calcium levels without substantially changing the affinity of calcium-activated CaM for eNOS [30, 50].”
BackgroundZhou, M., Widmer, R. J., Xie, W., Widmer, A. J., Miller, M. W., Schroeder, F., Parker, J. L., & Heaps, C. L. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00754.2009 · Cited by 25
Liu, J., Gao, Y., Negash, S., Longo, L. D., & Raj, J. U. (2009) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.90333.2008 · Cited by 25
Stromal cell–derived factor 2 is critical for Hsp90-dependent eNOS activation
Siragusa, M., Fröhlich, F., Park, E. J., Schleicher, M., Walther, T. C., & Sessa, W. C. (2015) · Science Signaling · doi:10.1126/scisignal.aaa2819 · Cited by 24
“After 20 hours, cells were transduced with 25 MOI of Ad.eGFP-CTA, eNOS S1179A, or eNOS S1179D, and after an additional 20 hours, culture media were replaced with fresh culture media and cells were allowed to grow for 72 hours until confluent.”
BackgroundInfluentialSelf-citationAntiobesogenic Role of Endothelial Nitric Oxide Synthase
Sansbury, B. E., & Hill, B. G. (2014) · Vitamins and hormones · doi:10.1016/b978-0-12-800254-4.00013-1 · Cited by 26
Phosphorylation Controls Endothelial Nitric-oxide Synthase by Regulating Its Conformational Dynamics
Haque, M. M., Ray, S. S., & Stuehr, D. J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.737361 · Cited by 24
“The cytochrome c reductase activity of eNOS is repressed in its native state, but the repression is relieved by CaM binding (20,26).”
BackgroundResultInfluentialMilano, G., Bianciardi, P., Rochemont, V., Vassalli, G., von Segesser, . K., Corno, A. F., Guazzi, M., & Samaja, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027910 · Cited by 24
“Although eNOS can be phosphorylated in multiple sites, its phosphorylation at Ser(1177), as probed in this study, indicates the effective degree of electron flow through eNOS [29].”
BackgroundMusicki, B., Champion, H. C., Hsu, L. L.-Y., Bivalacqua, T. J., & Burnett, A. L. “. (2010) · The Journal of Sexual Medicine · doi:10.1111/j.1743-6109.2010.02123.x · Cited by 24
Calcium Signaling in Mast Cells: Focusing on L-Type Calcium Channels
Suzuki, Y., Inoué, T., & Ra, C. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2888-2_44 · Cited by 24
Dedkova, E. N., Wang, Y. G., Ji, X., Blatter, L. A., Samarel, A. M., & Lipsius, S. L. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2006.126805 · Cited by 24
“…C© 2007 The Physiological Society 342 E. N. Dedkova and others J Physiol 580.1 cells activation of PI-(3)K–Akt signalling enhances the sensitivity of eNOS to Ca2+ (Dimmeler et al. 1999) as well as increases eNOS catalytic activity, and reduces the dissociation of CaM from eNOS (McCabe et al. 2000).”
BackgroundInfluentialAmelio, D., Garofalo, F., Capria, C., Tota, B., & Imbrogno, S. (2012) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2012.10.037 · Cited by 24
Cale, J. M., & Bird, I. M. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00942.2005 · Cited by 23
Zhou, X., Yuan, D., Wang, M., & He, P. (2012) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00300.2012 · Cited by 22
McCullagh, K. J. A., Cooney, R., & O’Brien, T. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.11.002 · Cited by 22
Taylor, S., Dixon, H. M., Yoganayagam, S., Price, N., & Lang, D. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.05.026 · Cited by 22
“Negative regulation occurs through increased eNOS phosphorylation at Ser114/6 (Li et al., 2007) and Thr495/7 (Fleming et al., 2001), while positive regulation occurs through increased phosphorylation at Ser633/5 and Ser1177/9 (Boo et al., 2003; Dimmeler et al., 1999; Fulton et al., 1999; McCabe et al., 2000).”
BackgroundInfluentialSánchez‐Ruiloba, L., Aicart-Ramos, C., García‐Guerra, L., Pose‐Utrilla, J., Rodríguez‐Crespo, I., & Iglesias, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095191 · Cited by 21
“In the case of eNOS, mimicking the phosphorylation of Ser(1179) by introducing an acidic residue in recombinant purified enzymes directly enhances enzyme activity and alters the sensitivity of the enzyme to Ca, rendering its activity maximal at sub-physiological concentrations of this cation [82].”
BackgroundNavarro‐Lérida, I., Martínez‐Moreno, M., Ventoso, I., Alvarez, A. M., & Rodríguez‐Crespo, I. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-12-1102 · Cited by 21
“Mutation of Ser-1179 to aspartic acid, which mimics the phosphorylated state, results in enhanced NOS3 reductase activity and NO production (McCabe et al., 2000).”
BackgroundThe anandamide effect on NO/cGMP pathway in human platelets
Signorello, M. G., Giacobbe, E., Passalacqua, M., & Leoncini, G. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23008 · Cited by 21
“Insulin increases platelet eNOS activity through eNOSser1177 residue phosphorylation [McCabe et al., 2000] and this effect is dependent on activation of AKT and partially on AMP-dependent protein kinase activation [Fleming et al., 2003].”
BackgroundFornero, S., Bassino, E., Gallo, M. P., Ramella, R., Levi, R. C., & Alloatti, G. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712802429984 · Cited by 21
“In particular, phosphorylation of Ser1177 stimulates the flux of electrons within the reductase domain, increases the Ca 2+ sensitivity of the enzyme, and represents an additional and independent mechanism of eNOS activation [16, 17].”
BackgroundmTORc1 activity is necessary and sufficient for phosphorylation of eNOSS1177
Decker‐Rockefeller, B., & Pumiglia, K. M. (2018) · Physiological Reports · doi:10.14814/phy2.13733 · Cited by 20
“Phosphorylation of eNOS has been shown to stabilize the interaction between eNOS and the calcium-binding protein, making it less dependent upon calcium (McCabe et al. 2000).”
BackgroundMazrouei, S., Sharifpanah, F., Caldwell, R. W., Franz, M., Shatanawi, A., Muessig, J. M., Fritzenwanger, M., Schulze, P. C., & Jung, C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.05.004 · Cited by 21
d’Uscio, L. V., Smith, L. A., & Katušić, Z. S. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00588.2011 · Cited by 20
Chen, J., Lu, L., Zhang, C., Zhu, X., & Zhuang, S. (2021) · Nanoscale · doi:10.1039/d1nr01965a · Cited by 20
Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart
Goyal, A., Semwal, B. C., & Yadav, H. (2015) · Human & Experimental Toxicology · doi:10.1177/0960327115597980 · Cited by 20
“This phosphorylation not only activates eNOS but also increases the efficiency of activation by calcium ion/calmodulin.(34) Thus, estrogen increases bioavailability of NO and decreases myocardial injury.”
BackgroundDas, A. K., Gopalakrishnan, B., Druhan, L. J., Wang, T., Pascali, F. D., Rockenbauer, A., Racoma, I. O., Varadharaj, S., Zweier, J. L., Cardounel, A. J., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12572 · Cited by 19
“Activation by eNOS Ser(1179) phosphorylation results from the enhanced electron flux through the reductase domain and inhibition of calmodulin-dissociation from the enzyme in a calcium-independent fashion (Fulton et al., 1999; McCabe et al., 2000) and is mediated by several upstream kinases, among which PI3/Akt has be…”
InfluentialChen, Y., Jiang, B., Zhuang, Y., Hu, P., & Chen, W. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179978 · Cited by 19
Nieto-Veloza, A., Wang, Z., Zhong, Q., D'Souza, D. H., Krishnan, H. B., & Día, V. P. (2022) · Food Science and Human Wellness · doi:10.1016/j.fshw.2022.06.008 · Cited by 19
Cardioprotective effect of sonic hedgehog ligand in pig models of ischemia reperfusion
Ghaleh, B., Thireau, J., Cazorla, O., Soleti, R., Scheuermann, V., Bizé, A., Sambin, L., Roubille, F., Andriantsitohaina, R., Martínez, M. C., et al. (2020) · Theranostics · doi:10.7150/thno.40461 · Cited by 19
“1177 by AKT has been shown to increase NO production [23,24].”
BackgroundGlimepiride activates eNOS with a mechanism Akt but not caveolin-1 dependent
Salani, B., Repetto, S., Cordera, R., & Maggi, D. C. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.07.149 · Cited by 19
Inoué, T., Suzuki, Y., Yoshimaru, T., & Ra, C. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.1007667 · Cited by 19
“Consistent with this view, we here demonstrated that in mast cells, antigen induces phosphorylation of eNOS at Ser1177 (equivalent to human eNOS-Ser1179), the well-characterized event essential for maximal activation of the enzyme [30, 31 ].”
BackgroundLow nitric oxide: a key factor underlying copper-deficiency teratogenicity
Yang, S. J., Keen, C. L., Lanoue, L., Rucker, R. B., & Uriu‐Adams, J. Y. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.08.031 · Cited by 19
“eNOS phosphorylation at serine 1177 enhances electron flux through the reductase domain, and is a key factor affecting NOS activity [46].”
BackgroundSu, Y., Kondrikov, D., & Block, E. R. (2007) · Science s STKE · doi:10.1126/stke.4042007pe52 · Cited by 19
“which is a major determinant of NOS-3 enzymatic activity (18, 26).”
BackgroundAkiyama, M., Eguchi, D., Weiler, D. A., O’Brien, T., Kovesdi, I., Scotland, R. S., Sessa, W. C., & Katušić, Z. S. (2002) · Stroke · doi:10.1161/hs0402.105553 · Cited by 19
Self-citationZhuo, W., Song, X., Zhou, H., & Luo, Y. (2011) · Biochemical Society Transactions · doi:10.1042/bst0391376 · Cited by 17
Protein Ser/Thr phosphatases PPEF interact with calmodulin
Kutuzov, M. A., Solov'eva, O. V., Andreeva, A. V., & Bennett, N. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00338-8 · Cited by 17
Devika, N. T., Amresh, P., Hassan, M. I., & Ali, B. M. J. (2014) · Journal of Molecular Modeling · doi:10.1007/s00894-014-2470-7 · Cited by 16
“Multiple signaling protein kinases—including protein kinase B (Akt/PKB), protein kinase A (PKA), protein kinase G, AMP activated protein kinase, and CaM kinase II—regulate eNOS by phosphorylating serine residues (S615, S633, and S1177) localized in the reductase domain stimulated by a variety of humoral, mechanical, a…”
BackgroundBeijert, I. J., Mert, S., Huang, V., Karimian, N., Geerts, S., Hafiz, E. O. A., Markmann, J. F., Yeh, H., Porte, R. J., & Uygun, K. (2018) · Transplantation Direct · doi:10.1097/txd.0000000000000779 · Cited by 17
“When ser-1177 is phosphorylated in response to increased shear stress, nitric oxide (NO) production increases twofold to threefold above baseline levels.(27) Steady laminar flow enhances the expression of vasoprotective genes eNOS and TM through KLF2 and regulates the activation of eNOS.”
BackgroundSomatostatin modulates PI3K-Akt, eNOS and NHE activity in the ciliary epithelium
Ghosh, S., Choritz, L., Geibel, J. P., & Coca‐Prados, M. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.05.002 · Cited by 16
Modulation of endothelial nitric oxide synthase by fibronectin
Viji, R. I., Kumar, V. B. S., Kiran, M. S., & Sudhakaran, P. R. (2008) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-008-9967-2 · Cited by 16
“Phosphorylation of Ser residue in the reductase domain causes a 2–3 fold increase in eNOS activity [35] and phosphorylation of Thr residue within the calmodulin-binding domain is reported to negatively regulate its activity [10, 36].”
BackgroundHorinouchi, T., Mazaki, Y., Terada, K., & Miwa, S. (2020) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b20-00522 · Cited by 16
Anwar, A., Yameen, D., Masood, M., Parvez, S., & Haque, M. M. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.148589 · Cited by 16
Yoshida, M., Nakamura, K., Miyoshi, T., Yoshida, M., Kondo, M., Akazawa, K., Kimura, T., Ohtsuka, H., Ohno, Y., Miura, D., et al. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01132-2 · Cited by 16
Functional status of microvascular vasomotion is impaired in spontaneously hypertensive rat
Liu, M., Zhang, X., Wang, B., Wu, Q., Li, B., Li, A., Zhang, H., & Xiu, R. (2017) · Scientific Reports · doi:10.1038/s41598-017-17013-w · Cited by 14
Redox-sensitive mechanisms underlying vascular dysfunction in heart failure
Konradi, J., Mollenhauer, M., Baldus, S. E., & Klinke, A. (2015) · Free Radical Research · doi:10.3109/10715762.2015.1027200 · Cited by 14
Ladage, D., Braunroth, C., Lenzen, E., Berghöfer, S., Gräf, C., Bloch, W., & Brixius, K. (2012) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y2012-138 · Cited by 15
Karakus, S., Musicki, B., & Burnett, A. L. “. (2018) · British Journal of Urology · doi:10.1111/bju.14433 · Cited by 13
eNOS Gene Variant in Patients with Coronary Artery Disease
Abolhalaj, M., Amoli, M. M., & Amiri, P. (2012) · Journal of Biomarkers · doi:10.1155/2013/403783 · Cited by 14
“A functional polymorphism within eNOS gene is a 27 bp VNTR on its intron 4 which has been shown to be associated with various diseases.”
BackgroundSheng, J., Arshad, F., Braun, J. E. A., & Braun, A. P. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00561.2007 · Cited by 13
“Moreover, phosphorylation of eNOS at Ser1177 appears to be an important activation mechanism used by several agonists to stimulate de novo NO production (7, 15, 21, 33 ), and modification of this site has been documented in both isolated endothelial cells and intact arterial tissue (9, 15, 17, 47).”
BackgroundProtein kinase D activity controls endothelial nitric oxide synthesis
Aicart-Ramos, C., Sánchez-Ruiloba, L., Gómez-Parrizas, M., Zaragoza, C., Iglesias, T., & Rodríguez-Crespo, I. (2014) · Journal of Cell Science · doi:10.1242/jcs.148601 · Cited by 12
“Hence, PKD1 phosphorylation of eNOS activates the enzyme and further confirms the proposal that phosphorylation of Ser1179 mediates the Ca2+-independent activation of eNOS (Dimmeler et al., 1999; Fulton et al., 1999; McCabe et al., 2000).”
InfluentialChronic Lead Exposure Decreases the Vascular Reactivity of Rat Aortas: The Role of Hydrogen Peroxide
Nunes, K. Z., Nunes, D. O., Silveira, E. A., Almenara, C. C. P., Filho, G. B. B., Vassallo, D. V., & Fioresi, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120965 · Cited by 12
“This result was associated with increased iNOS protein expression and increased eNOS phosphorylation at Ser1177, the primary regulator of NO production [22,23,8].”
BackgroundHe, A., Zuo, D., Liang, X., Guo, Y., Suxin, L., & Xia, Y. (2020) · Microvascular Research · doi:10.1016/j.mvr.2020.104075 · Cited by 13
Schmidt, K., Gibraeil, H. D., & Mayer, B. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(01)00936-4 · Cited by 12
Thébault, S. C., González, C., García, C., Zamarripa, D. A., Nava, G., Vaca, L. A., López‐Casillas, F., de la Escalera, G. M., & Clapp, C. (2011) · Pharmaceuticals · doi:10.3390/ph4071052 · Cited by 12
“Phosphorylation of eNOS at Ser(1179) renders eNOS more sensitive to Ca/calmodulin binding [23,24] and contributes to eNOS-vascular functions [49,50] and to BK signaling [22].”
BackgroundModrego, J., Azcona, L. J., Martín‐Palacios, N., Zamorano‐León, J. J., Segura, A., Rodríguez, P., Guerra, R., Tamargo, J. L., Macaya, C., & López-Farré, A. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0082574 · Cited by 12
“In this regard, it is well known that when NOS3 is phosphorylated at Ser(1177) position, the flux of electrons through the reductase domain is increased and, consequently, the NO production [22].”
BackgroundCharacterization of Drosophila nitric oxide synthase: a biochemical study
Sengupta, R., Sahoo, R., Mukherjee, S., Regulski, M., Tully, T., Stuehr, D. J., & Ghosh, S. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01003-9 · Cited by 14
NO Synthesis and NOS Regulation
Förstermann, U., Li, H., Schwarz, P. M., & Kleinert, H. (2003) · Springer eBooks · doi:10.1007/0-306-48412-9_7 · Cited by 12
Ren, J. T., Zhang, X., Scott, G. I., Esberg, L. B., Ren, B. H., Culver, B. W., & Chen, A. F. (2004) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200402000-00002 · Cited by 12
“speculated that such serine phosphorylation may diminish the auto-inhibition of calmodulin binding.(28) Although direct link-”
BackgroundThe Ever‐Expanding Influence of the Endothelial Nitric Oxide Synthase
Rafea, R., Siragusa, M., & Fleming, I. (2025) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.70029 · Cited by 12
“…proteins targeted by nitric oxide, as well as the cellular processes affected. as a surrogate index of eNOS activation, this is an error as although phosphorylation does increase electron flow through the reductase domain to increase NO production [48–50], it is not essential for enzyme activation.”
Mesquita, A. P. S., Matsuoka, M., Lopes, S. A., Filho, P. C. A. P., Cruz, A. S., Nader, H. B., & Lopes, C. C. (2022) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x2021e11612 · Cited by 11
“This phosphorylation reduces the enzyme’s Ca- dependence, increases the electron flux from the reductase domain to the oxygenase domain, and consequently increases the NO production (22).”
BackgroundDobrucki, L. W., Marsh, B. J., & Kalinowski, L. (2009) · PubMed · Cited by 11
Ray, S. S., Sengupta, R., Tiso, M., Haque, M. M., Sahoo, R., Konas, D. W., Aulak, K. S., Regulski, M., Tully, T., Stuehr, D. J., et al. (2007) · Biochemistry · doi:10.1021/bi700805x · Cited by 11
Yao, K., Xu, B., Liu, Y., & Ferro, A. (2003) · PubMed · Cited by 11
Early pathological mechanisms in a mouse model of heart failure with preserved ejection fraction
Rosas, P. C., Neves, L. A. A., Patel, N. A., Tran, D., Pereira, C. H., Bonilla, K., Zheng, J., Sun, J., Alvarado, F. J., & Banach, K. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00318.2024 · Cited by 11
Laird, P.-A. R., Wall, R. M., & Craige, S. M. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156360 · Cited by 14
Suzuki, Y., Inoué, T., & Ra, C. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.11.003 · Cited by 10
“Moreover, the NO generation was accompanied by increased phosphorylation of eNOS at Ser1177, an important mechanism for increasing eNOS activity [37,38] and increased phosphorylation of Akt at Ser473, the residue linked to eNOS activation [39,40].”
BackgroundNitrooleate Mediates Nitric Oxide Synthase Activation in Endothelial Cells
Shin, E., Yeo, E.-J., Lim, J., Chang, Y. H., Park, H., Shim, E., Chung, H., Hwang, H. J., Chun, J., & Hwang, J. (2014) · Lipids · doi:10.1007/s11745-014-3893-8 · Cited by 10
15‐Lipoxygenase‐Mediated Modification of HDL3 Impairs eNOS Activation in Human Endothelial Cells
Cutuli, L., Pirillo, A., Uboldi, P., Kuehn, H., & Catapano, A. L. (2014) · Lipids · doi:10.1007/s11745-014-3888-5 · Cited by 10
“eNOS activity is also regulated by phosphorylation [11], and the Akt-mediated phosphorylation of Ser [14] positively regulates NO production [15].”
BackgroundAngiogenic Response of Endothelial Cells to Fibronectin
Kumar, V. B. S., Viji, R. I., Kiran, M. S., & Sudhakaran, P. R. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3381-1_10 · Cited by 10
White, A. R., Ryoo, S., Bugaj, L. J., Attarzadeh, D. O., Thiyagarajan, S., Chen, K., Attwater, S., Abbot, B., Li, D., Champion, H. C., et al. (2010) · European Journal of Applied Physiology · doi:10.1007/s00421-010-1514-7 · Cited by 10
“Acute HLU upregulated Pi-NOS-3 1177, a site known to be important in the activation of NOS (Fleming et al. 2001; McCabe et al. 2000 ).”
BackgroundInfluentialIschemic preconditioning: Interruption of various disorders
Goyal, A., & Agrawal, N. (2016) · Journal of the Saudi Heart Association · doi:10.1016/j.jsha.2016.09.002 · Cited by 10
“This phosphorylation not only activates eNOS but also increases the efficiency of activation by Ca/calmodulin [160].”
BackgroundYoshida, M., Nakamura, K., Miyoshi, T., Yoshida, M., Kondo, M., Akazawa, K., Kimura, T., Ohtsuka, H., Ohno, Y., Miura, D., et al. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01181-7 · Cited by 10
Nishino, Y., Yamamoto, K., Kimura, S., Kikuchi, A., Shiro, Y., & Iyanagi, T. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2007.05.021 · Cited by 9
Chen, R. (2005) · Science in China Series C Life Sciences · doi:10.1360/062004-36 · Cited by 9
Nitric oxide and the brain. Part 2: Effects following neonatal brain injury—friend or foe?
Angelis, D., Savani, R. C., & Chalak, L. F. (2020) · Pediatric Research · doi:10.1038/s41390-020-1021-4 · Cited by 9
“The most well-known target of NO is the reaction with the iron atom of guanylyl cyclase to activate it and produce cyclic guanosine monophosphate (cGMP) that promotes the vasodilatory functions of NO.”
BackgroundInfluentialGarcía, C., Núñez‐Anita, R. E., Thébault, S. C., Zamarripa, D. A., Jeziorsky, M. C., de la Escalera, G. M., & Clapp, C. (2013) · Endocrine · doi:10.1007/s12020-013-9964-4 · Cited by 8
“In particular, the phosphorylation of bovine eNOS at serine residue 1179 (S1177 in the human sequence) activates eNOS catalytic function by enhancing the internal rate of eNOS electron transfer and by inhibiting calmodulin dissociation from eNOS [12].”
Background
Metadata
- Authors
- McCabe, T. J., Fulton, D., Roman, L. J., & Sessa, W. C.
- Affiliations
- Yale University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Sessa, William C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 275
- Issue
- 9
- Pages
- 6123-6128
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2090688283
- Cited by
- 387
- References
- 32
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 5 · 2022: 11 · 2021: 13 · 2020: 18 · 2019: 4 · 2018: 11 · 2017: 8 · 2016: 9 · 2015: 16 · 2014: 18 · 2013: 14 · 2012: 21
- FWCI
- 14.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (HL61371, HL64793)
- National Heart, Lung, and Blood Institute (HL-61371, HL-64793, R01HL064793, HL 57665, R01HL057665)
- National Institute of General Medical Sciences (R01GM052419)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- endothelial nitric oxide synthase, eNOS phosphorylation, Akt, nitric oxide production, electron flux, reductase domain, calcium-independent activation, cytochrome c reduction, L-arginine
- MeSH terms
- Animals, Calcium, Calmodulin, Cattle, Egtazic Acid, Electrons, Enzyme Activation, Kinetics, Mutation, NADH Dehydrogenase, NADP, Nitric Oxide, Phosphorylation, Proto-Oncogene Proteins, Protein Serine-Threonine Kinases, Nitric Oxide Synthase, Dimerization, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, Static Electricity
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
