Jump to Main Content
Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes
- Gonzalez, Daniel R., Beigi, Farideh, Treuer, Adriana V., Hare, Joshua M.
- Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.51 pp. 20612-20617
- calcium, cardiomyocytes, heart diseases, homeostasis, neuronal nitric oxide synthase, oxidation, phenotype, phosphorylation, sarcoplasmic reticulum, stoichiometry, thiols
- Altered Ca²⁺ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via S-nitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca²⁺ homeostasis. Diastolic Ca²⁺ levels are elevated in NOS1⁻/⁻ and NOS1/NOS3⁻/⁻ but not NOS3⁻/⁻ myocytes compared with wild-type (WT), suggesting diastolic Ca²⁺ leakage. Measured leak was increased in NOS1⁻/⁻ and NOS1/NOS3⁻/⁻ but not in NOS3⁻/⁻ myocytes compared with WT. Importantly, NOS1⁻/⁻ and NOS1/NOS3⁻/⁻ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1⁻/⁻ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca²⁺ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.