From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation.

All eukaryotic cells have adapted the use of the calcium ion (Ca2+) as a universal signaling element through the evolution of a toolkit of Ca2+ sensor, buffer and effector proteins. Among these toolkit components, integral and peripheral proteins decorate biomembranes and coordinate the movement of Ca2+ between compartments, sense these concentration changes and elicit physiological signals. These changes in compartmentalized Ca2+ levels are not mutually exclusive as signals propagate between compartments. For example, agonist induced surface receptor stimulation can lead to transient increases in cytosolic Ca2+ sourced from endoplasmic reticulum (ER) stores; the decrease in ER luminal Ca2+ can subsequently signal the opening surface channels which permit the movement of Ca2+ from the extracellular space to the cytosol. Remarkably, the minuscule compartments of mitochondria can function as significant cytosolic Ca2+ sinks by taking up Ca2+ in a coordinated manner. In non-excitable cells, inositol 1,4,5 trisphosphate receptors (IP3Rs) on the ER respond to surface receptor stimulation; stromal interaction molecules (STIMs) sense the ER luminal Ca2+ depletion and activate surface Orai1 channels; surface Orai1 channels selectively permit the movement of Ca2+ from the extracellular space to the cytosol; uptake of Ca2+ into the matrix through the mitochondrial Ca2+ uniporter (MCU) further shapes the cytosolic Ca2+ levels. Recent structural elucidations of these key Ca2+ toolkit components have improved our understanding of how they function to orchestrate precise cytosolic Ca2+ levels for specific physiological responses. This chapter reviews the atomic-resolution structures of IP3R, STIM1, Orai1 and MCU elucidated by X-ray crystallography, electron microscopy and NMR and discusses the mechanisms underlying their biological functions in their respective compartments within the cell.