In many cell types, the rise in cytosolic Ca due to opening of Ca release-activated Ca (CRAC) channels drives a plethora of responses, including secretion, motility, energy production, and gene expression. The amplitude and time course of the cytosolic Ca rise is shaped by the rates of Ca entry into and removal from the cytosol. However, an extended bulk Ca rise is toxic to cells. Here, we show that the plasma membrane Ca ATPase (PMCA) pump plays a major role in preventing a prolonged cytosolic Ca signal following CRAC channel activation. Ca entry through CRAC channels leads to a sustained sub-plasmalemmal Ca rise but bulk Ca is kept low by the activity of PMCA4b. Despite the low cytosolic Ca, membrane permeability to Ca is still elevated and Ca continues to enter through CRAC channels. Ca-dependent NFAT activation, driven by Ca nanodomains near the open channels, is maintained despite the return of bulk Ca to near pre-stimulation levels. Our data reveal a central role for PMCA4b in determining the pattern of a functional Ca signal and in sharpening local Ca gradients near CRAC channels, whilst protecting cells from a toxic Ca overload.
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| http://dx.doi.org/10.1093/function/zqac040 | DOI Listing |
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