The Ca2+ export pump PMCA clears near-membrane Ca2+ to facilitate store-operated Ca2+ entry and NFAT activation

Pumped out to activateAs a regulator of many facets of cellular activity, the concentration of cytosolic calcium ions (Ca2+) is tightly controlled by pumps and channels in organelles and the plasma membrane. An influx of Ca2+ to the cytosol triggers various signaling pathways. Curiously, Go et al. found that the Ca2+ extrusion pump PMCA4 in the plasma membrane promoted, rather than inhibited, the Ca2+-induced activation of T cells. PMCA4-mediated clearance of membrane-proximal Ca2+ pools triggered endoplasmic reticulum–resident Ca2+ sensor/channel duo STIM1/Orai1 to release stored Ca2+, thereby activating an immune response–associated transcription factor in cultured T cells. These findings reveal a coupling between a plasma membrane Ca2+ pump and an organellar Ca2+ storage machinery.Ca2+ signals, which facilitate pluripotent changes in cell fate, reflect the balance between cation entry and export. We found that overexpression of either isoform of the Ca2+-extruding plasma membrane calcium ATPase 4 (PMCA4) pump in Jurkat T cells unexpectedly increased activation of the Ca2+-dependent transcription factor nuclear factor of activated T cells (NFAT). Coexpression of the endoplasmic reticulum–resident Ca2+ sensor stromal interaction molecule 1 (STIM1) with the PMCA4b splice variant further enhanced NFAT activity; however, coexpression with PMCA4a depressed NFAT. No PMCA4 splice variant dependence in STIM1 association was observed, whereas partner of STIM1 (POST) preferentially associated with PMCA4b over PMCA4a, which enhanced, rather than inhibited, PMCA4 function. A comparison of global and near-membrane cytosolic Ca2+ abundances during store-operated Ca2+ entry revealed that PMCA4 markedly depressed near-membrane Ca2+ concentrations, particularly when PMCA4b was coexpressed with STIM1. PMCA4b closely associated with both POST and the store-operated Ca2+ channel Orai1. Furthermore, POST knockdown increased the near-membrane Ca2+ concentration, inhibiting the global cytosolic Ca2+ increase. These observations reveal an unexpected role for POST in coupling PMCA4 to Orai1 to promote Ca2+ entry during T cell activation through Ca2+ disinhibition.