Modulation of SERCA: implications for the failing human heart

Abstract

Human heart failure is characterized by distinct alterations in the intracellular homeostasis and key regulators of the sarcoplasmic reticulum Ca²⁺ sequestration mechanisms. Systolic peak Ca²⁺ is reduced, diastolic Ca²⁺ levels are increased and diastolic Ca²⁺ decay is prolonged. Recently specific changes in the expression, function and modulation of SR Ca²⁺-ATPase (SERCA) have been elucidated. As such, in a variety of studies SERCA expression appeared to be decreased in the failing human heart, although these findings have been discussed controversially depending on the studied tissue, especially with respect to the non-failing samples and regional variation in the obtained samples. However, consistent findings of a diminished Ca²⁺ dependent SERCA activation were found. Increasing evidence has been provided that one of the underlying mechanisms for a decreased activation of SERCA is its altered regulation. With respect to this, the modulations through phospholamban and Ca²⁺-dependent protein kinase II (CaMK II) play a detrimental role in regulating SERCA function. Phospholamban phosphorylation of SERCA at the serine-16 and threonine-17 site is diminished in human heart failure resulting in decreases in the apparent affinity for Ca²⁺ of the SR Ca²⁺ uptake rates. In contrast, activation of CaMK II leads to an increased maximal velocity of SR Ca²⁺ sequestration that may enhance SR Ca²⁺-load. Additional regulation has been recently elucidated by changes in the apparent coupling ratio of Ca²⁺ transported per ATP hydrolysed. This review summarizes recent advances in the understanding how SERCA is modulated under physiological and pathophysiological conditions.