Abstract
SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency.
Highlights
The Sarco(Endo)plasmic Reticulum (SR) Ca2+ ATPase (SERCA) is a Ca2+ pump that uses the energy of ATP hydrolysis to translocate two Ca2+ ions from the cytosol to the SR lumen
SERCA2 activity has been recently suggested to be affected by acetylation/deacetylation mechanisms [11,15], no experimental evidence has so far been provided
We show that histone deacetylase (HDAC) inhibition promotes SERCA2 acetylation
Summary
The Sarco(Endo)plasmic Reticulum (SR) Ca2+ ATPase (SERCA) is a Ca2+ pump that uses the energy of ATP hydrolysis to translocate two Ca2+ ions from the cytosol to the SR lumen. It is composed of a single polypeptide weighing approximately 110 kDa and organized into four different domains: one transmembrane domain composed of ten alpha-helices, one nucleotide (ATP) binding site, one phosphorylation/catalytic domain that drives ATP hydrolysis, and one actuator domain involved in the gating mechanism that regulates calcium binding and release [1,2]. Alterations in SERCA2a are recognized among the major factors contributing to ventricular dysfunction in several heart diseases, like diabetic cardiomyopathy [5,6] and heart failure [7,8]
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