S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ

Erickson, Jeffrey R.; Nichols, C. Blake; Uchinoumi, Hitoshi; Stein, Matthew L.; Bossuyt, Julie; Bers, Donald M.

doi:10.1074/jbc.m115.650234

Cited by 82 publications

(79 citation statements)

References 36 publications

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“…Furthermore, consistent with the SR Ca 2+ leak data above, the NOS inhibitor L-NAME (100 μM) prevented the Epac activation of CaMKII (Figure 5B) and the NO-donor SNAP mimicked the CaMKII activation by both ISO and 8-CPT. This also shows that SNAP prevented further CaMKII activation by 8-CPT (Figure 5C), consistent with no further 8-CPT activation of already S -nitrosylated CaMKII [6, 7, 25]. Note also that PKA inhibition (H89) did not significantly reduce ISO-induced CaMKII activation (Figure 5C).…”

Section: Resultssupporting

confidence: 75%

“…This raised the idea of β-arrestin mediated signaling to CaMKII [24], as a parallel pathway from (β-AR to Akt and NOS1; Fig 1). Recent studies that have revealed the molecular mechanism by which S -nitrosylation occurs and mediates CaMKII activation [7, 25], localization of NOS1 at the junctional SR domain,[9] and robust evidence for cardiac CaMKIIδ in regulating RyR2 have solidified our understanding of the bottom part of the NOS1-RyR pathway.…”

Section: Introductionmentioning

confidence: 99%

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β-Adrenergic induced SR Ca 2+ leak is mediated by an Epac-NOS pathway

Pereira

Bare

Galice

et al. 2017

Journal of Molecular and Cellular Cardiology

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Cardiac β-adrenergic receptors (β-AR) and Ca2+-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca2+ signaling. Elevated diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca2+ leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1). Here we tested whether Epac and NOS function in a single series pathway to increase β-AR induced and CaMKII-dependent SR Ca2+ leak. Leak was measured as both Ca2+ spark frequency and tetracaine-induced shifts in SR Ca2+, in mouse and rabbit ventricular myocytes. Direct Epac activation by 8-CPT (8-(4-chlorophenylthio)-2′-O-methyl-cAMP) mimicked β-AR-induced SR Ca2+ leak, and both were blocked by NOS inhibition. The same was true for myocyte CaMKII activation (assessed via a FRET-based reporter) and ryanodine receptor phosphorylation. Inhibitor and phosphorylation studies also implicated phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) downstream of Epac and above NOS activation in this pathway. We conclude that these two independently characterized parallel pathways function mainly via a single series arrangement (β-AR-cAMP-Epac-PI3K-Akt-NOS1-CaMKII) to mediate increased SR Ca2+ leak. Thus, for β-AR activation the cAMP-PKA branch effects inotropy and lusitropy (by effects on Ca2+ current and SR Ca2+-ATPase), this cAMP-Epac-NOS pathway increases pathological diastolic SR Ca2+leak. This pathway distinction may allow novel SR Ca2+ leak therapeutic targeting in treatment of arrhythmias in heart failure that spare the inotropic and lusitropic effects of the PKA branch.

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Section: Resultssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

β-Adrenergic induced SR Ca 2+ leak is mediated by an Epac-NOS pathway

Pereira

Bare

Galice

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…However, whether this C290 nitrosylation induced CaMKII activation is also involved in β-adrenergic stimulation evoked myocyte death remains unclear. A recent study revealed that, besides cysteine 290, cysteine 273 can also be S-nitrosylated [40]. In contrast to C290 nitrosylation, C273 nitrosylation does not activate CaMKII, but inhibits Ca 2+ /calmodulin dependent activation of CaMKII.…”

Section: Introductionmentioning

confidence: 99%

“…Our view is that in vivo studies will be required to more completely elucidate the role of nitric oxide regulation of CaMKII in cardiac pathophysiology. Cysteine 290 can also be oxidized by hydrogen peroxide, resulting in Ca 2+ /calmodulin autonomous CaMKII activation [40]. Further research will be necessary to illuminate how the post-translational modifications in the regulatory domain interact with each other.…”

Section: Introductionmentioning

confidence: 99%

CaMKII is a nodal signal for multiple programmed cell death pathways in heart

Feng

Anderson

2017

Journal of Molecular and Cellular Cardiology

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Sustained Ca2+/calmodulin dependent kinase II (CaMKII) activation plays a central role in the pathogenesis of a variety of cardiac diseases. Emerging evidence suggests CaMKII evoked programmed cell death, including apoptosis and necroptosis, is one of the key underlying mechanisms for the detrimental effect of sustained CaMKII activation. CaMKII integrates β-adrenergic, Gq coupled receptor, reactive oxygen species (ROS), hyperglycemia, and pro-death cytokine signaling to elicit myocardial apoptosis by intrinsic and extrinsic pathways. New evidence demonstrates CaMKII is also a key mediator of receptor interacting serine/threonine kinase 3 (RIP3) induced myocardial necroptosis. The role of CaMKII in cell death is dependent upon subcellular localization and varies across isoforms and splice variants. While CaMKII is now an extensively validated nodal signal for promoting cardiac myocyte death, the upstream and downstream pathways and targets remain incompletely understood, demanding further investigation.

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“…Serine 280 (S280) can be modified during hyperglycemia by UDP- N -acetylglucosamine [11]. NO can activate CaMKII by nitrosylating C290 [12, 13, 14, 15]. Furthermore, NO can prevent CaMKII activation by nitrosylating C273, potentially allowing NO to confer coincidence detection properties that enhance spatial resolution for Ca 2+ and NO signaling [15].…”

Section: Camkii Is Activated By Rosmentioning

confidence: 99%