Signaling ER Store Depletion to Plasma Membrane Orai Channels

Cells maintain an inward Ca²⁺ gradient from the extracellular fluid to the cytosol, entrenched by the action of plasma membrane pumps/transporters that actively "pump out" Ca²⁺ and organellar pumps/transporters that mold the Ca²⁺ transients by storing it away in intracellular reservoirs. Exhaustibility of endoplasmic reticulum (ER) Ca²⁺ reserve is an essential feature that orchestrates cellular signaling initiated by Ca²⁺ entry. STIM1 can recruit ORAI channels into clusters, and both puncta and clusters spatially correspond with the sites of Ca²⁺ entry. ER Ca²⁺ depletion is sensed by the Ca²⁺-binding luminal EF-hand domain of STIM1, a disruption of which leads to a constitutive activation of STIM1. This chapter surveys the wealth of structural and biophysical studies to offer a mechanistic overview of STIM and ORAI functioning, focusing on the architectural changes these proteins undergo in response to store depletion. Coexpression of STIM1 and ORAI1 proteins is sufficient for generating SOCE current of large amplitude across various cellular systems.