Sarcoplasmic reticulum Ca<sup>2<b>+</b></sup>-ATPase from rabbit skeletal muscle modified by peroxynitrite

Zizkova, Petronela; Viskupičová, Jana; Blaskovic, D; Štrosová, Miriam; Žarković, Neven; Horáková, Ľubica

doi:10.3109/14756366.2013.827676

Cited by 4 publications

(1 citation statement)

References 36 publications

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“…Our results demonstrate that SERCA enzymatic activity is significantly reduced in DJ-1β mutant flies as well as in DJ-1- deficient SH-SY5Y neuron-like cells compared to controls. These results indicate that SERCA carbonylation leads to its inactivation in those PD models, as found in mammals (Žižková et al, 2014, 2018). Furthermore, we show that activation of SERCA with a specific allosteric activator of this protein (CDN1163) is capable to suppress PD-related phenotypes in fly and human cell models based on DJ-1 deficiency.…”

Section: Introductionmentioning

confidence: 61%

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Solana-Manrique

Muñoz-Soriano

et al. 2020

Preprint

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DJ-1 is a causative gene for familial Parkinson’s disease (PD) with different functions, standing out its role against oxidative stress (OS). Accordingly, PD model flies harboring a mutation in the DJ-1β gene (the Drosophila ortholog of human DJ-1) show high levels of OS markers like protein carbonylation, a common post-translational modification that may alter protein function. To increase our understanding of PD pathogenesis as well as to discover potential therapeutic targets for pharmacological intervention, we performed a redox proteomic assay in DJ-1β mutant flies. Among the proteins that showed increased carbonylation levels in PD model flies, we found SERCA, an endoplasmic reticulum Ca2+ channel that plays an important role in Ca2+ homeostasis. Several studies have supported the involvement of Ca2+ dyshomeostasis in PD. Interestingly, a functional link between DJ-1 and Ca2+ homeostasis maintenance was previously reported. Thus, we decided to study the relation between SERCA activity and PD physiopathology. Our results showed that SERCA enzymatic activity is significantly reduced in DJ-1β mutant flies, probably as a consequence of OS-induced carbonylation, as well as in a human cell PD model based on DJ-1-deficiency. Indeed, higher carbonylation levels of SERCA were also observed in DJ-1-deficient SH-SY5Y neuron-like cells compared to controls. In addition, we demonstrated that SERCA activity was increased in both PD models after treatment with a specific activator of this protein, CDN1163. Consistently, CDN1163 was also able to restore PD-related phenotypes in PD model flies and to increase viability in the human cell PD model. Taken together, our results indicate that impaired SERCA activity in both familial PD models may play a role in PD physiopathology. In addition, we demonstrate that therapeutic strategies addressing SERCA activation could be beneficial to treat this disease as shown for CDN1163.

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Section: Introductionmentioning

confidence: 61%

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Solana-Manrique

Muñoz-Soriano

et al. 2020

Preprint

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Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives

Viskupičová

Májeková

Horáková

2014

J Muscle Res Cell Motil

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The effect of lipophilic rutin derivatives (acylated with fatty acid chain length of 16-22) on sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA1 isoform) compared to the parent molecule rutin was evaluated. Rutin derivatives caused concentration dependent decrease of SERCA1 activity (IC50 ~ 23-64 µM) and significant conformational alterations in the transmembrane region of the enzyme. Upon treatment by peroxynitrite, rutin derivatives exerted a hormetic effect, i.e. prevented enzyme activity decrease at low concentrations, while additionally inhibited at high concentrations. Concerning the posttranslational modifications of SERCA1, rutin esters: (i) induced a significant loss of free sulfhydryl groups, (ii) protected the enzyme from protein carbonyl formation, and (iii) prevented SERCA from tyrosine nitration (except R20:4 and R22:1). In silico study revealed a strong affinity of the derivative R20:4 to the transmembrane region of SERCA1, stabilized via hydrogen bonds with Glu90, Glu771, Thr778 and Thr848 residues. Interaction of rutin derivatives with Glu771, a residue involved in Ca(2+) binding, is likely to be responsible for the inhibitory effect of the esters.

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Rutin stimulates sarcoplasmic reticulum Ca2+-ATPase activity (SERCA1) and protects SERCA1 from peroxynitrite mediated injury

et al. 2014

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In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-)) mediated impairment of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1 isoform), especially related to posttranslational and conformational changes. Rutin concentration dependently protected ONOO(-) induced SERCA1 activity decrease with effective concentration EC50 of 18 ± 1.5 µM. Upon treatment with ONOO(-), this flavonoid also prevented SERCA1 from thiol group oxidation and significantly reduced tyrosine nitration and protein carbonyl formation. In the absence of ONOO(-), rutin (250 and 350 µM) stimulated SERCA1 activity at 2.1 mM [ATP] and 10 µM [Ca(2+)]free. According to changes in the kinetic parameters V max and K m with regard to [ATP], rutin (250 µM) increased the rate of enzyme catalysis and decreased the affinity of SERCA1 to ATP. FITC fluorescence decreased in the presence of rutin (150 and 250 µM), indicating conformational changes in the cytosolic ATP binding region of SERCA1. In silico study confirmed the binding of rutin in the cytosolic region of SERCA1, in the vicinity of the ATP binding site. Residue Glu183 localized within the conserved TGES loop was identified to play a key role in rutin-SERCA1 interaction (H-bond length of 1.7 Å), elucidating the ability of rutin to affect the affinity of SERCA1 to ATP. The binding of rutin in the proximity of Lys515 is likely to cause a decrease in FITC fluorescence.

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Sarcoplasmic reticulum Ca²⁺-ATPase from rabbit skeletal muscle modified by peroxynitrite

Cited by 4 publications

References 36 publications

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives

Rutin stimulates sarcoplasmic reticulum Ca2+-ATPase activity (SERCA1) and protects SERCA1 from peroxynitrite mediated injury

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Sarcoplasmic reticulum Ca2+-ATPase from rabbit skeletal muscle modified by peroxynitrite

Cited by 4 publications

References 36 publications

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives

Rutin stimulates sarcoplasmic reticulum Ca2+-ATPase activity (SERCA1) and protects SERCA1 from peroxynitrite mediated injury

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Sarcoplasmic reticulum Ca²⁺-ATPase from rabbit skeletal muscle modified by peroxynitrite