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Review
. 2013 May;46(5):237-43.
doi: 10.5483/bmbrep.2013.46.5.077.

SERCA2a: a prime target for modulation of cardiac contractility during heart failure

Woo Jin Park  1 , Jae Gyun Oh
Affiliations
Review

SERCA2a: a prime target for modulation of cardiac contractility during heart failure

Woo Jin Park et al. BMB Rep. 2013 May.

Abstract

Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca(2+) cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/ endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a) mediates Ca(2+) reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca(2+) uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure.

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Figures

Fig. 1.
Fig. 1.. Calcium signaling during excitation-contraction coupling. Calcium signaling plays an essential role in cardiac muscle contraction and relaxation. Ca2+ entry via LTCC triggers SR Ca2+ release through RyR, a process termed calcium-induced calcium release (CICR). CICR causes activation of contraction of myofilaments. SR Ca2+ uptake via SERCA2a and extrusion via NCX allow relaxation of myofilaments. CICR, Ca2+-induced Ca2+ release; LTCC, L-type Ca2+ channel; NCX, Na+-Ca2+ exchanger; PLB, phospholamban; RyR, ryanodine receptor; SERCA2a, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a; SR, sarcoplasmic reticulum; T-tubule, transverse tubule.
Fig. 2.
Fig. 2.. SERCA2a activity and calcium handling in heart failure. The dysregulation of SERCA2a is a hallmark of heart failure. Reduction in SR Ca2+ uptake results in systolic dysfunction as well as increased cytosolic Ca2+ level and susceptibility to apoptosis. In heart failure, SERCA2a activity and expression are decreased via negative regulation by upstream modulators. I-1, protein phosphatase inhibitor 1; PKCα, the α isotype of protein kinase C; PLB, phospholamban; PP1, protein phosphatase 1; SERCA2a, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a; SUMO, small ubiquitin- like modifier; RyR, ryanodine receptor.
Fig. 3.
Fig. 3.. Design of decoy peptides. The "L-shaped" structure of monomeric PLB is composed of a cytoplasmic helix, a connecting short loop, and a transmembrane helix. Blue box, ψPLB-SE was derived from the nine amino acids that compose the connecting loop. In the decoy peptide, the serine residue was replaced with a glutamine to mimic the peptide in its phosphorylated state (shown in green). The peptide was conjugated via a disulfide bond at the amino-termini to the cell penetrating peptide TAT (YG-RKKRRQRRR) to facilitate uptake of the peptide into cells.
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