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.