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

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.

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