Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation

Abstract

The cardiac SR Ca(2+)-ATPase (SERCA2a) regulates intracellular Ca(2+)-handling and thus, plays a crucial role in initiating cardiac contraction and relaxation. SERCA2a may be modulated through its accessory phosphoprotein phospholamban or by direct phosphorylation through Ca(2+)/calmodulin dependent protein kinase II (CaMK II). As an inhibitory component phospholamban, in its dephosphorylated form, inhibits the Ca(2+)-dependent SERCA2a function, while protein kinase A dependent phosphorylation of the phospho-residues serine-16 or Ca(2+)/calmodulin-dependent phosphorylation of threonine-17 relieves this inhibition. Recent evidence suggests that direct phosphorylation at residue serine-38 in SERCA2a activates enzyme function and enhances Ca(2+)-reuptake into the sarcoplasmic reticulum (SR). These effects that are mediated through phosphorylation result in an overall increased SR Ca(2+)-load and enhanced contractility. In human heart failure patients, as well as animal models with induced heart failure, these modulations are altered and may result in an attenuated SR Ca(2+)-storage and modulated contractility. It is also believed that abnormalities in Ca(2+)-cycling are responsible for blunting the frequency potentiation of contractile force in the failing human heart. Advanced gene expression and modulatory approaches have focused on enhancing SERCA2a function via overexpressing SERCA2a under physiological and pathophysiological conditions to restore cardiac function, cardiac energetics and survival rate.

Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

“…DOX has been consistently found to decrease SERCA2a mRNA and protein levels (Arai et al, 1998;Olson et al, 2005;Richard et al, 2011), and SERCA2a impairment is closely associated with decreased heart contractility in DOX cardiotoxicity (Frank et al, 2003;Periasamy & Huke, 2001). In this study, DOX treatment caused significant decrease (p50.05) of SERCA2a mRNA expression level in the DOX only-treated group which can partially explain the rise of cytosolic and mitochondrial calcium levels.…”

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

“…Compared with wild-type mice, AMϩ/Ϫ mice exhibited lower survival rates, which were accompanied by higher cardiac brain natriuretic peptide levels; higher heart weight/body weight ratios; greater left ventricular wall thickening; and reprogramming of specific cardiac genes. In particular, downregulation of the SERCA2 gene, which is associated with cardiac dysfunction, 25,26 was more apparent in the hearts of AMϩ/Ϫ mice. Using cultured cardiac myocytes from AMϩ/Ϫ mice, we confirmed directly that these cells show more pronounced hypertrophic responses to stressful stimuli.…”

Influência do tempo de exposição à obesidade sobre a função cardíaca de ratos

“…Esta proteína de ação enzimática pode ser modulada diretamente ou indiretamente por vários fatores. (86) A fosfolambam (PLB), também localizada na membrana do retículo sarcoplasmático (RS), inibe diretamente a afinidade entre a Serca2a e os íons cálcio, prejudicando a recaptura de Ca +2 para o RS. (228) Entretanto, a PLB em seu estado fosforilado, na serina-16 e/ou treonina-17, altera a inibição da Serca2a.…”

“…A fosforilação da PLB via sistema β-adrenérgico, na serina-16, altera o bloqueio exercido pela PLB em relação à Serca2a, permitindo a recaptura de cálcio para o RS. (86,229,230) Além disso, a modulação direta da Serca2a é acarretada pela fosforilação da PLB via calmodulina quinase dependente de Ca +2 , na treonina 17. (76,231) Outros agentes podem modular diretamente a atividade e expressão da Serca2a, entre eles, os hormônios tireoidianos, (232) a insulina (233) e nitrosilação.…”

“…(78,79) Alterações na quantidade ou função dos canais L têm sido implicadas em uma variedade de doenças cardiovasculares, como fibrilação atrial, insuficiência cardíaca e isquemia crônica. (80)(81)(82) Diversos modelos experimentais mostram que o canal L exerce papel fundamental na performance cardíaca e, qualquer defeito na função deste canal, pode conseqüentemente, acarretar disfunção cardíaca; (83)(84)(85) (86) entretanto, em ratos esta proteína é responsável pela recaptura de 92%. (75) Diversos modelos experimentais mostram que a disfunção cardíaca pode estar associada com aterações nos níveis e/ou atividade da Serca2a.…”