SERCA control of cell death and survival

Intracellular calcium (Ca²⁺⁾ is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca²⁺ dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca²⁺ homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca²⁺ concentrations are therefore tightly regulated by a number of Ca²⁺ handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca²⁺ storage organelles, which work in concert to fine tune a temporally and spatially precise Ca²⁺ signal. Chief amongst them is the sarco/endoplasmic reticulum (SR/ER) Ca²⁺ ATPase pump (SERCA) which actively re-accumulates released Ca²⁺ back into the SR/ER, therefore maintaining Ca²⁺ homeostasis. There are at least 14 different SERCA isoforms encoded by three ATP2A1-3 genes whose expressions are species- and tissue-specific. Altered SERCA expression and activity results in cellular malignancy and induction of ER stress and ER stress-associated apoptosis. The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus of this review. Ca²⁺ is a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca²⁺ homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders.