Nitrosylation of cardiac CaMKII at Cys290 mediates mechanical afterload‐induced increases in Ca<sup>2+</sup> transient and Ca<sup>2+</sup> sparks

Alim, Chidera C.; Ko, Christopher Y.; Hernández, Juliana Mira; Shen, Erin Y.; Baidar, Sonya; Chen‐Izu, Ye; Bers, Donald M.; Bossuyt, Julie

doi:10.1113/jp283427

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…The CaMKIIδ-C290A knock-in mice were generated by the UC Davis Mouse Biology Core and have been described previously. 20 CaMKIIδ-C273S animals were generated using CRISPR/Cas9 genome editing at the Australian Phenomics Facility (Australian National University, Australia). For all mouse resources described here and materials listed below, please see the Major Resources Table in the Supplemental Material.…”

Section: Methodsmentioning

confidence: 99%

“…19 S -nitrosylation at cysteine-290, following initial activation by Ca 2+ /CaM, causes autonomous activation of the kinase, consistent with the observation that NO exposure can enhance CaMKIIδ activity and increase Ca 2+ sparks. 11,13,20 In contrast, S -nitrosylation at cysteine-273 inhibits CaMKIIδ by preventing activation by Ca 2+ /CaM, 19 suggesting a dual role for NO in mediating CaMKIIδ activity that may be alternately protective or pathological depending on intracellular conditions.…”

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confidence: 99%

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Nitric Oxide Modulates Ca ²⁺ Leak and Arrhythmias via S-Nitrosylation of CaMKII

Power,

Asamudo,

Worthington

et al. 2023

Circulation Research

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Background: Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca 2+ release via S -nitrosylation of CaMKIIδ (Ca 2+ /calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of S -nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca 2+ handling and arrhythmogenesis before and during β-adrenergic receptor stimulation. Methods: We measured Ca 2+ -handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the S -nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S -nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L). Results: Both WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca 2+ transient response as well as increased Ca 2+ spark frequency. However, the increase in Ca 2+ spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca 2+ sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events. Conclusions: We conclude that prior S -nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor–induced arrhythmias, but that S -nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor–induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Nitric Oxide Modulates Ca ²⁺ Leak and Arrhythmias via S-Nitrosylation of CaMKII

Power,

Asamudo,

Worthington

et al. 2023

Circulation Research

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“… 42 Ca 2+ /calmodulin-dependent protein kinase II (CaMK II) is a serine/threonine protein kinase that can phosphorylate many proteins within cells, thereby increasing the intracellular calcium ion concentration. 43 After treating BMDMs with Yoda1 in calcium free medium, a decrease in the phosphorylation of Mob1 (a physiological substrate of Mst) was observed, indicating that eliminating extracellular Ca 2+ could inhibit the activation of Mst1/2 by Piezo1. These finding further confirmed that Ca 2+ was an important second messenger through which Piezo1 activates Mst1/2.…”

Section: Piezo1 Regulates Macrophage Involvement In the Inflammatory ...mentioning

confidence: 97%

Mechanical gated ion channel Piezo1: Function, and role in macrophage inflammatory response

Xie,

Hang

2024

Innate Immun

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Macrophages are present in many mechanically active tissues and are often subjected to varying degrees of mechanical stimulation. Macrophages play a crucial role in resisting pathogen invasion and maintaining tissue homeostasis. Piezo-type mechanosensitive channel component 1 (Piezo1) is the main cation channel involved in the rapid response to mechanical stimuli in mammals. This channel plays a crucial role in controlling blood pressure and motor performance and regulates urinary osmotic pressure and epithelial cell proliferation and division. In recent years, numerous studies have shown that in macrophages, Piezo1 not only plays a role in regulating the aforementioned physiological processes but also participates in multiple pathological processes such as inflammation and cancer. In this review, we summarize the research progress on Piezo1-mediated regulation of macrophage-mediated inflammatory responses through downstream signalling pathways and the aerobic glycolysis pathway.

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“…Disulfide bridge formation (inter-subunit and inter-channel cross linking), glutathionylation by glutathione (GSH), nitrosylation by nitric oxide (NO) and phosphorylation by ROS-and RNSactivated CaMKII can all contribute to an increased RyR channel activity [71][72][73][74][75][76].…”

Section: Redox Modificationsmentioning

confidence: 99%