Intracellular Ca2+ storage in health and disease: a dynamic equilibrium

Homeostatic control of the endoplasmic reticulum (ER) both as the site for protein handling (synthesis, folding, trafficking, disaggregation and degradation) and as a Ca2+ store is of crucial importance for correct functioning of the cell. Disturbance of the homeostatic control mechanisms leads to a vast array of severe pathologies. The Ca2+ content of the ER is a dynamic equilibrium between active uptake via Ca2+ pumps and Ca2+ release by a number of highly regulated Ca2+-release channels. Regulation of the Ca2+-release channels is very complex and several mechanisms are still poorly understood or controversial. There is increasing evidence that a number of unrelated proteins, either by themselves or in association with other Ca2+ channels, can provide additional Ca2+-leak pathways. The ER is a dynamic organelle and changes in its size and components have been described, either as a result of (de)differentiation processes affecting the secretory capacity of cells, or as a result of adaptation mechanisms to diverse stress conditions such as the unfolded protein response and autophagy. In this review we want to give an overview of the current knowledge of the (short-term) regulatory mechanisms that affect Ca2+-release and Ca2+-leak pathways and of the (long-term) adaptations in ER size and capacity. Understanding of the consequences of these mechanisms for cellular Ca2+ signaling could provide a huge therapeutic potential.