Microdomains of high intracellular calcium ion concentration, [Ca ²⁺ ] _i , have been hypothesized to occur in living cells exposed to stimuli that generate inositol 1,4,5-trisphosphate (IP ₃ ). Mitochondrially targeted recombinant aequorin was used to show that IP ₃ -induced Ca ²⁺ mobilization from intracellular stores caused increases of mitochondrial Ca ²⁺ concentration, [Ca ²⁺ ] _m , the speed and amplitude of which are not accounted for by the relatively small increases in mean [Ca ²⁺ ] _i . A similar response was obtained by the addition of IP ₃ to permeabilized cells but not by perfusion of cells with Ca ²⁺ at concentrations similar to those measured in intact cells. It is concluded that in vivo, domains of high [Ca ²⁺ ] _i are transiently generated close to IP ₃ -gated channels and sensed by nearby mitochondria; this may provide an efficient mechanism for optimizing mitochondrial activity upon cell stimulation.

Ca²⁺-ATPases (pumps) are key actors in the regulation of Ca²⁺in eukaryotic cells and are thus essential to the correct functioning of the cell machinery. They have high affinity for Ca²⁺and can efficiently regulate it down to very low concentration levels. Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently. Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts. The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca²⁺. The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump. These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca²⁺-signaling dysfunction. Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca²⁺homeostasis that are incompatible with cell life. However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca²⁺-controlling and/or processing machinery. They do not bring cells to immediate death but seriously compromise their normal functioning.