Figure 1.

Organellar Ca²⁺ buffering and intracellular Ca²⁺ dynamics. Ca²⁺ is stored within several different organelles including the endoplasmic reticulum (ER), ERGIC, the Golgi apparatus, mitochondria, and peroxisomes. A typical Ca²⁺ release pathway is shown at top: an extracellular ligand binds to its receptor, leading to production of IP₃, which binds to the IP₃R on the ER membrane, stimulating release of Ca²⁺ from the ER lumen. Note that the Golgi apparatus also contains IP₃R molecules and thus may contribute to Ca²⁺ release from stores; Golgi Ca²⁺ uptake occurs via SPCA pumps. As shown at left, Ca²⁺ released from the ER has several different fates, including regulation of gene transcription within the nucleus; uptake by mitochondria, which are typically closely apposed to the ER network and where Ca²⁺ can affect metabolism; or extrusion from the cell via Na⁺/Ca²⁺ exchanger plasma membrane proteins. Peroxisomes are known to maintain Ca²⁺ at higher levels than those of the cytoplasm, but how this gradient is developed and maintained is not yet known. Ca²⁺ levels are elevated in the ER, in the SR, in the ERGIC, and in the Golgi apparatus, with most Ca²⁺ bound to buffering proteins, as shown within these organelles. The store-operated Ca²⁺ entry (SOC) is also represented. In response to depleted ER Ca²⁺ stores, an ER luminal Ca²⁺ sensor, STIM1, oligomerizes and migrates to subplasmalemmal punctae where it communicates with Orai1. Orai1 functions as a plasma membrane Ca²⁺ channel that allows for Ca²⁺ entry from the extracellular milieu into the cytoplasm, where it is taken up by SERCA into the ER lumen. BiP/GRP78 binding protein/glucose-regulated protein of 78-kDa; CRT, calreticulin; ERGIC, endoplasmic reticulum/Golgi intermediate complex; GRP94, glucose-regulated protein of 94-kDa; IP₃, inositol trisphosphate; IP₃R, inositol trisphosphate receptor; NCX, Na⁺/Ca²⁺ exchanger; P54/NEFA, DNA binding/EF hand/acidic amino acid rich region protein; PDI, protein disulfide isomerase; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase; SPCA, secretory pathway Ca²⁺-transport ATPase; STIM1, stromal interacting molecule 1.