A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban

Kaneko, Minoru; Yamamoto, Hideaki; Sakai, Hiroki; Kamada, Yusuke; Tanaka, Toshiki; Fujiwara, Shuji; Yamamoto, Satoshi; Takahagi, Hiroki; Igawa, Hideyuki; Kasai, Shizuo; Noda, Masakuni; Inui, Makoto; Nishimoto, Tetsuya

doi:10.1016/j.ejphar.2017.07.035

Cited by 16 publications

(17 citation statements)

References 45 publications

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“…Alternative to gene delivery, small molecule SERCA2a agonists have been reported (Ferrandi et al, 2013;Kaneko et al, 2017), but molecular details of their working mechanism are lacking. SERCA2a (encoded by the ATP2A2 gene) is expressed in cardiac, smooth and slow-twitch skeletal muscles, while SERCA1a (ATP2A1) is the major isoform in fast-twitch skeletal muscles.…”

Section: Introductionmentioning

confidence: 99%

Structures of the heart specific SERCA2a Ca²⁺-ATPase

Nissen

Raeymaecker

Kotsubei

et al. 2018

Preprint

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The sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA‐stabilized E2−AlF4− form (3.3 Å) and the Ca2+‐occluded [Ca2]E1‐AMPPCP form (4.0 Å). The structures are similar to the skeletal muscle isoform SERCA1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA1a and SERCA2a. We find that several isoform‐specific residues are acceptor sites for post‐translational modifications. In addition, molecular dynamics simulations predict that isoform‐specific residues support distinct intramolecular interactions in SERCA2a and SERCA1a. Our experimental observations further indicate that isoform‐specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA2a and SERCA1a.

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Section: Introductionmentioning

confidence: 99%

Structures of the heart specific SERCA2a Ca²⁺-ATPase

Nissen

Raeymaecker

Kotsubei

et al. 2018

Preprint

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“…4 ), in agreement with prior findings in myostatin-null mice [ 17 , 42 ]. Phospholamban (PhLB) is a sarcoplasmic reticulum membrane protein that regulates calcium uptake through inhibition of SERCA activity [ 43–45 ]. PhLB is negatively regulated by its phosphorylation (Ser16/Th17) mediated by PKA [ 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques

Guo

Pencina

Gagliano‐Jucá

et al. 2018

Journal of the Endocrine Society

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An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two-dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety.

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“…Very recently, a pyridone derivative was reported to activate the SERCA2a isoform by attenuating the inhibitory effect of PLN (Kaneko et al, 2017 ). In vitro and in vivo experiments have demonstrated that the pyridone derivative stimulates the Ca 2+ -dependent ATPase activity of cardiac SR vesicles, increases Ca 2+ transients of isolated adult rat cardiomyocytes and accelerates contraction and relaxation of isolated perfused rat hearts.…”

Section: Pharmacological Stimulation Of Serca Activitymentioning

confidence: 99%

Drug Interactions With the Ca2+-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA)

Tadini‐Buoninsegni

Smeazzetto

Gualdani

et al. 2018

Front. Mol. Biosci.

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The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is an intracellular membrane transporter that utilizes the free energy provided by ATP hydrolysis for active transport of Ca2+ ions from the cytoplasm to the lumen of sarco(endo)plasmic reticulum. SERCA plays a fundamental role for cell calcium homeostasis and signaling in muscle cells and also in cells of other tissues. Because of its prominent role in many physiological processes, SERCA dysfunction is associated to diseases displaying various degrees of severity. SERCA transport activity can be inhibited by a variety of compounds with different chemical structures. Specific SERCA inhibitors were identified which have been instrumental in studies of the SERCA catalytic and transport mechanism. It has been proposed that SERCA inhibition may represent a novel therapeutic strategy to cure certain diseases by targeting SERCA activity in pathogens, parasites and cancer cells. Recently, novel small molecules have been developed that are able to stimulate SERCA activity. Such SERCA activators may also offer an innovative and promising therapeutic approach to treat diseases, such as heart failure, diabetes and metabolic disorders. In the present review the effects of pharmacologically relevant compounds on SERCA transport activity are presented. In particular, we will discuss the interaction of SERCA with specific inhibitors and activators that are potential therapeutic agents for different diseases.

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A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban

Cited by 16 publications

References 45 publications

Structures of the heart specific SERCA2a Ca²⁺-ATPase

Structures of the heart specific SERCA2a Ca²⁺-ATPase

Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques

Drug Interactions With the Ca2+-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA)

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A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban

Cited by 16 publications

References 45 publications

Structures of the heart specific SERCA2a Ca2+-ATPase

Structures of the heart specific SERCA2a Ca2+-ATPase

Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques

Drug Interactions With the Ca2+-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA)

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Product

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Structures of the heart specific SERCA2a Ca²⁺-ATPase

Structures of the heart specific SERCA2a Ca²⁺-ATPase