Multiple and diverse coexpression, location, and regulation of additional SERCA2 and SERCA3 isoforms in nonfailing and failing human heart

Among the players involved in Ca2+ homeostasis in heart tissue are SERCA (sarco/endoplasmic reticulum Ca2+ ATPase)-type Ca2+ pumps. Until recently, human heart was known to coexpress major SERCA2a and minor SERCA2b isoforms. Here, we will summarize data showing that nonfailing human heart is equipped with an increasing variety of SERCA isoforms comprised new SERCA2 (ATP2A2) and SERCA3 (ATP2A3) gene products. The novel 3′-ends of the human SERCA2 and -3 genes, the corresponding mRNAs and the carboxyl termini of the SERCA2a-2c and SERCA3a-3f isoforms will be presented. The intrinsic characteristics and effects on cellular Ca2+ homeostasis of the SERCA2 and SERCA3 recombinant isoforms will be summarized. Evidence for the expression of SERCA2c and SERCA3a, -3d, and -3f mRNAs and/or endogenous proteins in the human heart will be summarized, the latter having being visualized thanks to newly generated isoform-specific antibodies. We will show how the strategic localization of the SERCA2c, SERCA3a, -3d, and -3f isoforms in cytoplasmic compartments, and the nucleus enables them to contribute to subsarcolemmal, cytoplasmic, and nuclear Ca2+ signalling in the human heart and isolated cardiomyocytes. Comparative expressions of the additional SERCA isoforms in some failing hearts will also be summarized. Lastly, we will present what is known regarding the role the SERCA2c, SERCA3a, -3d, or -3f isoforms in cardiac muscle pathophysiology. To focus on up-to-date topics, this multi-SERCA system of human heart may sustain a distinct internal endoplasmic reticulum (ER) compartment in cardiomyocytes, as well as potential compensatory mechanisms and both SR/ER abnormalities in heart failure.