ArticleThe Journal of biological chemistry2012
Modulation of heme/substrate binding cleft of neuronal nitric-oxide synthase (nNOS) regulates binding of Hsp90 and Hsp70 proteins and nNOS ubiquitination.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- Heat shock protein 70s are modifiers of endothelial function in Fabry disease.Kidney international · 2026Article
- Degradation of nNOS in the PVN of Rats With Heart Failure: Role of CHIP.Hypertension (Dallas, Tex. : 1979) · 2025Article
- HSP70-Mediated Autophagy-Apoptosis-Inflammation Network and Neuroprotection Induced by Heat Acclimatization.Biology · 2025Review
- Nitric oxide synthase and its function in animal reproduction: an update.Frontiers in physiology · 2023Review
- Indoleamine dioxygenase and tryptophan dioxygenase activities are regulated through GAPDH- and Hsp90-dependent control of their heme levels.Free radical biology & medicine · 2022Article
- Prevention of the return of extinguished fear by disrupting the interaction of neuronal nitric oxide synthase with its carboxy-terminal PDZ ligand.Molecular psychiatry · 2021Article
- Plasma heat shock protein response to euglycemia in type 2 diabetes.BMJ open diabetes research & care · 2021Article
- Heat Shock Protein 70 (HSP70) Induction: Chaperonotherapy for Neuroprotection after Brain Injury.Cells · 2020Review
- Hsp70:CHIP Ubiquitinates Dysfunctional but Not Native Neuronal NO Synthase.Molecular pharmacology · 2020Article
- Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.Nature neuroscience · 2020Article
- Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update.Journal of clinical medicine · 2020Review
- Unbiased proteomics identifies plasminogen activator inhibitor-1 as a negative regulator of endothelial nitric oxide synthase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- RETRACTION: The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model.International journal of molecular sciences · 2020Article
- Heat shock protein signaling in brain ischemia and injury.Neuroscience letters · 2020Review
- Article
- Nitric oxide synthase enzymology in the 20 years after the Nobel Prize.British journal of pharmacology · 2019Review
- Chaperone Activity and Dimerization Properties of Hsp90Molecular pharmacology · 2018Article
- Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states.Expert opinion on therapeutic targets · 2017Review
- Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy.Physiological reviews · 2016Review
- Heat Shock Protein 90 Associates with the Per-Arnt-Sim Domain of Heme-free Soluble Guanylate Cyclase: IMplications for Enzyme Maturation.The Journal of biological chemistry · 2015Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Like other nitric-oxide synthase (NOS) enzymes, neuronal NOS (nNOS) turnover and activity are regulated by the Hsp90/Hsp70-based chaperone machinery, which regulates signaling proteins by modulating ligand binding clefts (Pratt, W. B., Morishima, Y., and Osawa, Y. (2008) J. Biol. Chem. 283, 22885-22889). We have previously shown that nNOS turnover is due to Hsp70/CHIP-dependent ubiquitination and proteasomal degradation. In this work, we use an intracellular cross-linking approach to study both chaperone binding and nNOS ubiquitination in intact HEK293 cells. Treatment of cells with N(G)-nitro-L-arginine, a slowly reversible competitive inhibitor that stabilizes nNOS, decreases both nNOS ubiquitination and binding of Hsp90, Hsp70, and CHIP. Treatment with the calcium ionophore A23187, which increases Ca(2+)-calmodulin binding to nNOS, increases nNOS ubiquitination and binding of Hsp90, Hsp70, and CHIP in a manner that is specific for changes in the heme/substrate binding cleft. Both Hsp90 and Hsp70 are bound to the expressed nNOS oxygenase domain, which contains the heme/substrate binding cleft, but not to the reductase domain, and binding is increased to an expressed fragment containing both the oxygenase domain and the calmodulin binding site. Overexpression of Hsp70 promotes nNOS ubiquitination and decreases nNOS protein, and overexpression of Hsp90 inhibits nNOS ubiquitination and increases nNOS protein, showing the opposing effects of the two chaperones as they participate in nNOS quality control in the cell. These observations support the notion that changes in the state of the heme/substrate binding cleft affect chaperone binding and thus nNOS ubiquitination.
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