SERCA control of cell death and survival.

Intracellular calcium (Ca is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca concentrations are therefore tightly regulated by a number of Ca handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca storage organelles, which work in concert to fine tune a temporally and spatially precise Ca signal. Chief amongst them is the sarco/endoplasmic reticulum (SR/ER) Ca ATPase pump (SERCA) which actively re-accumulates released Ca back into the SR/ER, therefore maintaining Ca 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. Ca is a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca 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.