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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“Conversely, AMP-activated kinase phosphorylates eNOS at threonine 495, leading to diminished activity of the enzyme (Fleming et al. 2001).”
Background
Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation
Mazrouei, 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
Gomisin A induces Ca2+-dependent activation of eNOS in human coronary artery endothelial cells
Park, J. Y., Shin, H. K., Choi, Y. W., Lee, Y. J., Bae, S. S., Han, J., & Kim, C. D. (2009) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2009.06.028 · Cited by 21
“…al., 1997) and an Akt kinase-dependent erine phosphorylation of eNOS in position 1177 (i.e., Ser1177 eNOS) Michel et al., 1997; Fulton et al., 1999; Fleming et al., 2001). n the present study, we demonstrated that GA rapidly induced NOS translocation within 5 min after GA application with little…”
Background
Involvement of Nitric Oxide in Iodine Deficiency-Induced Microvascular Remodeling in the Thyroid Gland: Role of Nitric Oxide Synthase 3 and Ryanodine Receptors
Craps, J., Wilvers, C., Joris, V., Jongh, B. D., Vanderstraeten, J., Lobysheva, I. I., Balligand, J., Sonveaux, P., Gilon, P., Many, M., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1729 · Cited by 21
Does nitroglycerin therapy hit the endothelium?∗∗Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Münzel, T. F. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01507-8 · Cited by 21
Arginase II protein regulates Parkin-dependent p32 degradation that contributes to Ca2+-dependent eNOS activation in endothelial cells
Koo, B., Won, M., Kim, Y., & Ryoo, S. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab163 · Cited by 20
Ca2+-activated K+ channels of small and intermediate conductance control eNOS activation through NAD(P)H oxidase
Gaete, P. S., Lillo, M. A., Ardiles, N. M., Pérez, F. R., & Figueroa, X. F. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.036 · Cited by 20
Regulation of arterial blood pressure by Akt1-dependent vascular relaxation
Ha, J. M., Kim, Y. W., Lee, D. H., Yun, S. J., Kim, E. K., Jin, I. H., Kim, J. H., Kim, C. D., Shin, H. K., & Bae, S. S. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0798-3 · Cited by 20
“Calcium/ calmodulin-dependent protein kinase II and AMPactivated protein kinase increase eNOS activity by phosphorylation on Ser1177 [3, 4 ]. In addition, Ser1177 is phosphorylated by Akt protein kinase which plays a central role in survival, growth, differentiation, and proliferation [5–7].”
Background
Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A
Kang, J. J., Shu, L., Park, J. L., Shayman, J. A., & Bodary, P. F. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00185.2013 · Cited by 20
Impressic Acid, a Lupane-Type Triterpenoid from Acanthopanax koreanum, Attenuates TNF-α-Induced Endothelial Dysfunction via Activation of eNOS/NO Pathway
Jin, S. W., Pham, H., Choi, J. H., Lee, G. H., Han, E. H., Cho, Y. H., Chung, Y. C., Kim, Y. H., & Jeong, H. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225772 · Cited by 19
Effect of Pioglitazone on Nitroglycerin-Induced Impairment of Nitric Oxide Bioavailability by a Catheter-Type Nitric Oxide Sensor
Ikejima, H., Imanishi, T., Tsujioka, H., Kuroi, A., Muragaki, Y., Mochizuki, S., Goto, M., Yoshida, K., & Akasaka, T. (2008) · Circulation Journal · doi:10.1253/circj.72.998 · Cited by 19
Norfuraneol dephosphorylates eNOS at threonine 495 and enhances eNOS activity in human endothelial cells
Schmitt, C. A., Heiß, E. H., Aristei, Y., Severin, T., & Dirsch, V. M. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn326 · Cited by 19
Endothelial-transcytosed myeloperoxidase activates endothelial nitric oxide synthase via a phospholipase C-dependent calcium signaling pathway
Thai, T., Zhong, F., Dang, L., Chan, E., Ku, J., Malle, E., Geczy, C. L., Keaney, J. F., & Thomas, S. R. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.448 · Cited by 20
CYTOCHROMES P450 ARE DIFFERENTLY EXPRESSED IN NORMAL AND VARICOSE HUMAN SAPHENOUS VEINS: LINKAGE WITH VARICOSIS
Thiebault, C., Ferrari, L., Boutherin‐Falson, O., Kockx, M. M., Desquand‐Billiald, S., Fichelle, J. M., Nottin, R., Renaud, J., Batt, A., & Visvikis‐Siest, S. (2004) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2004.03996.x · Cited by 19
Interplay of endothelial and inducible nitric oxide synthases modulates the vascular response to ischaemia–reperfusion in the rabbit lung
Sedoris, K. C., Gozal, E., Ovechkin, A. V., Theile, A. R., & Roberts, A. M. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02348.x · Cited by 18
“Full activation requires its coupling with Thr495 dephosphorylation (Fleming et al. 2001, Michell et al. 2001; Li et al. 2004b).”
Background
Activation of eNOS in endothelial cells exposed to ionizing radiation involves components of the DNA damage response pathway
Nagane, M., Yasui, H., Sakai, Y., Yamamori, T., Niwa, K., Hattori, Y., Kondo, T., & Inanami, O. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.12.002 · Cited by 19
The Role of Vasospasm and Microcirculatory Dysfunction in Fluoropyrimidine-Induced Ischemic Heart Disease
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The Effects of Acidosis on eNOS in the Systemic Vasculature: A Focus on Early Postnatal Ontogenesis
Gaynullina, D. K., Tarasova, O. S., Shvetsova, A. A., Borzykh, A. A., & Schubert, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23115987 · Cited by 18
“The kinase that phosphorylates eNOS at Thr495 is claimed to be protein kinase C (PKC); PKC inhibitors considerably increase the synthesis of NO [45].”
Background
Central hypotensive effects of neuropeptide Y are modulated by endothelial nitric oxide synthase after activation by ribosomal protein S6 kinase
Cheng, P., Wu, A. T. H., Lu, P., Yang, Y., Ho, W., Lin, H., Hsiao, M., & Tseng, C. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02077.x · Cited by 18
“When the intracellular calcium concentration increases, caveolin is displaced by calciumcalmodulin, which results in stimulatory phosphorylation at Ser of eNOS (Fleming et al., 2001; Cheng et al., 2011).”
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Vitamin D suppresses oxidative stress-induced microparticle release by human umbilical vein endothelial cells
Jia, X.-Y., Xu, J., Gu, Y., Gu, X., Li, W., & Wang, Y. (2016) · Biology of Reproduction · doi:10.1093/biolre/bio142604 · Cited by 18
c-Jun N-terminal kinase 2 phosphorylates endothelial nitric oxide synthase at serine 116 and regulates nitric oxide production
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Na+/H+ exchanger inhibitor induces vasorelaxation through nitric oxide production in endothelial cells via intracellular acidification-associated Ca2+ mobilization
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Retinoic acid decreases nitric oxide production in endothelial cells: a role of phosphorylation of endothelial nitric oxide synthase at Ser1179
Cho, D., Choi, Y. J., Jo, S. A., Nam, J., Jung, S., & Jo, I. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.099 · Cited by 18
Rho-kinase Activation Contributes to Lps-Induced Impairment of Endothelial Nitric Oxide Synthase Activation by Endothelin-1 in Cultured Hepatic Sinusoidal Endothelial Cells
Kwok, W., & Clemens, M. G. (2014) · Shock · doi:10.1097/shk.0000000000000252 · Cited by 18
Roles of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II in inhibitory avoidance learning in rats
Tan, S.-E. (2007) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3280142636 · Cited by 18
“It is of interest to notice that neuronal NOS can be regulated via phosphorylation by CaM-kinase II (Komeima et al., 2000; Fleming et al., 2001; Agostino et al., 2004).”
BackgroundResult
Involvement of the proteasome in activation of endothelial nitric oxide synthase
Govers, R., de Bree, P., & Rabelink, T. J. (2003) · Life Sciences · doi:10.1016/s0024-3205(03)00644-1 · Cited by 18
REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE: INVOLVEMENT OF PROTEIN KINASE G 1β, SERINE 116 PHOSPHORYLATION AND LIPID STRUCTURES
John, T. A., Ibe, B. O., & Raj, J. U. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04801.x · Cited by 18
Impaired nitric oxide‐ and endothelium‐derived hyperpolarizing factor‐dependent dilation of renal afferent arteriole in Dahl salt‐sensitive rats
Ozawa, Y., Hayashi, K., Kanda, T., Homma, K., Takamatsu, I., Tatematsu, S., Yoshioka, K., Kumagai, H., Wakino, S., & Saruta, T. (2004) · Nephrology · doi:10.1111/j.1440-1797.2004.00292.x · Cited by 18
Sex‐Specific Differences in Endothelial Function Are Driven by Divergent Mitochondrial Ca 2+ Handling
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Phenylephrine activates eNOS Ser1177 phosphorylation and nitric oxide signaling in renal hypertensive rat aorta
Silva, B. R., Pernomian, L., Grando, M. D., & Bendhack, L. M. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.05.040 · Cited by 17
CCN1 acutely increases nitric oxide production via integrin αvβ3–Akt–S6K–phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis
Hwang, S., Lee, H.-J., Kim, G., Won, K., Park, Y. S., & Jo, I. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.08.005 · Cited by 18
GPER inhibits diabetes-mediated RhoA activation to prevent vascular endothelial dysfunction
Li, Z., Cheng, L., Liang, H., Duan, W., Hu, J., Zhi, W., Yang, J., Liu, Z., Zhao, M., & Liu, J. (2015) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2015.12.002 · Cited by 17
“Subsequent phosphorylation of the stimulatory site Ser1177 optimizes eNOS activity (Fleming et al., 2001; Mount et al., 2007).”
Background
Sibutramine provokes apoptosis of aortic endothelial cells through altered production of reactive oxygen and nitrogen species
Morikawa, Y., Shibata, A., Okumura, N., Ikari, A., Sasajima, Y., Suenami, K., Sato, K., Takekoshi, Y., El-Kabbani, O. A. L., & Matsunaga, T. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.11.003 · Cited by 17
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Therapeutic potential of targeting the renin angiotensin system in portal hypertension
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DT-13 ameliorates TNF-α-induced nitric oxide production in the endothelium in vivo and in vitro
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Calcineurin-mediated dephosphorylation of eNOS at serine 116 affects eNOS enzymatic activity indirectly by facilitating c-Src binding and tyrosine 83 phosphorylation
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“Agonist- and flow-stimulated phosphorylation at S1179, for example, increases eNOS activity (Fulton et al., 1999; Dimmeler et al., 1999) whereas phosphorylation at T497 reduces enzyme activity (Harris et al., 2001b; Fleming et al., 2001; Michell et al., 2001).”
Background
Role of platelet endothelial form of nitric oxide synthase in collagen–platelet interaction: regulation by phosphorylation
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Arsenite Acutely Decreases Nitric Oxide Production via the ROS—Protein Phosphatase 1—Endothelial Nitric Oxide Synthase-Thr 497 Signaling Cascade
Seo, J., Lee, J. Y., Sung, M.-S., Byun, C. J., Cho, D., Lee, H.-J., Park, J., Cho, H.-S., Cho, S.-J., & Jo, I. (2014) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2014.106 · Cited by 16
“Previously, PP1, PP2A or PKC was reported to be involved in alteration in eNOS-Thr497 phosphorylation (Fleming et al., 2001; Michell et al., 2001).”
Background
Somatostatin modulates PI3K-Akt, eNOS and NHE activity in the ciliary epithelium
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Modulation of endothelial nitric oxide synthase by fibronectin
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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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