The Ca ²⁺ export pump PMCA clears near-membrane Ca ²⁺ to facilitate store-operated Ca ²⁺ entry and NFAT activation

Abstract

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.

The Plasma Membrane Ca2+ Pump PMCA4b Regulates Melanoma Cell Migration through Remodeling of the Actin Cytoskeleton

“…Similarly, another study on mesenchymal-like chemoresistant IGROV1 ovarian cancer cells showed enhanced cell migration as a result of enhanced focal adhesion turnover mediated by SOCE [ 62 ]. It has been suggested that PMCA4b has the ability to decrease near-membrane Ca 2+ concentration in response to SOCE [ 63 ] that may explain, at least partly, the enhanced focal adhesion and reduced motility of the PMCA4b expressing melanoma cells.…”

Plasma membrane Ca2+ ATPase 1 (PMCA1) but not PMCA4 is critical for B‐cell development and Ca2+ homeostasis in mice

“…Both PMCA1 and PMCA4 are expressed in mouse T cells [8]. Moreover, in human Jurkat T cells, PMCA4 is the leading isoform for calcium clearance and NFAT transcriptional activity [9]. However, mouse B cells can differ from T cells in their requirements for various Ca 2+ handling proteins; for example, the mitochondrial Na + ‐Ca 2+ exchanger NCLX is required for B‐cell migration but not T‐cell migration [10].…”

Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anti‐cancer immunity in vivo

“…However, qPCR analysis of their expression levels failed to support this hypothesis (Fig EV3A); increases in STIM1, Orai3, and PMCA4a were observed in EGR1 −/− , but not EGR4 −/− cells. A modest increase in partner of STIM1 (POST) expression was observed, but this seemed unlikely to account for observed changes in TCR‐mediated Ca 2+ responses reported here. We then considered the possibility that sustained Ca 2+ entry may require compensatory maintenance of membrane potential through potassium channel activity.…”