Plasma Membrane Ca²⁺ ATPase Activity Enables Sustained Store-operated Ca²⁺ Entry in the Absence of a Bulk Cytosolic...

In many cell types, the rise in cytosolic Ca²⁺ due to opening of Ca²⁺ release-activated Ca²⁺ (CRAC) channels drives a plethora of responses, including secretion, motility, energy production, and gene expression. The amplitude and time course of the cytosolic Ca²⁺ rise is shaped by the rates of Ca²⁺ entry into and removal from the cytosol. However, an extended bulk Ca²⁺ rise is toxic to cells. Here, we show that the plasma membrane Ca²⁺ ATPase (PMCA) pump plays a major role in preventing a prolonged cytosolic Ca²⁺ signal following CRAC channel activation. Ca²⁺ entry through CRAC channels leads to a sustained sub-plasmalemmal Ca²⁺ rise but bulk Ca²⁺ is kept low by the activity of PMCA4b. Despite the low cytosolic Ca²⁺, membrane permeability to Ca²⁺ is still elevated and Ca²⁺ continues to enter through CRAC channels. Ca²⁺-dependent NFAT activation, driven by Ca²⁺ nanodomains near the open channels, is maintained despite the return of bulk Ca²⁺ to near pre-stimulation levels. Our data reveal a central role for PMCA4b in determining the pattern of a functional Ca²⁺ signal and in sharpening local Ca²⁺ gradients near CRAC channels, whilst protecting cells from a toxic Ca²⁺ overload.