Ca2+-pumping by PMCA-neuroplastin complexes operates in the kiloHertz-range

Cristina E. Constantin, Barbara Schmidt, Yvonne Schwarz, Harumi Harada, Astrid Kollewe, Catrin S. Müller, Sebastian Henrich, Botond Gaal, Akos Kulik, Dieter Bruns, Uwe Schulte, Heiko Rieger () and Bernd Fakler ()
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Cristina E. Constantin: University of Freiburg
Barbara Schmidt: Saarland University
Yvonne Schwarz: Saarland
Harumi Harada: University of Freiburg
Astrid Kollewe: University of Freiburg
Catrin S. Müller: University of Freiburg
Sebastian Henrich: University of Freiburg
Botond Gaal: University of Freiburg
Akos Kulik: University of Freiburg
Dieter Bruns: Saarland
Uwe Schulte: University of Freiburg
Heiko Rieger: Saarland University
Bernd Fakler: University of Freiburg

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Ca2+-ATPases in the plasma membrane extrude Ca2+ ions from the cytosol to the extracellular space thereby terminating Ca2+-signals and controlling Ca2+-homeostasis in any type of cell. Recently, these Ca2+-pumps have been identified as protein complexes of the transporting subunits PMCAs1-4 and the single-span membrane proteins Neuroplastin (NPTN) or Basigin that are obligatory for efficient trafficking of the pump complexes to the surface membrane. Quantitative investigation of the pumping velocity controlling the time course of Ca2+-signals, however, has remained unresolved. Here we show, using Ca2+-activated K+ channels as fast native reporters of intracellular Ca2+ concentration(s) together with membrane-tethered fluorescent Ca2+-indicators, that under cellular conditions PMCA2-NPTN complexes can clear Ca2+ in the low millisecond-range. Computational modeling exploiting EM-derived densities of Ca2+-source(s) and Ca2+-transporters in freeze-fracture replicas translated these fast kinetics into transport rates for individual PMCA2-NPTN pumps of more than 5000 cycles/s. Direct comparison with the Na+/Ca2+-exchanger NCX2, an alternate-access transporter with established cycling rates in the kHz range, indicated similar efficiencies in Ca2+-transport. Our results establish PMCA2-NPTN complexes, the most abundant Ca2+-clearing tool in the mammalian brain, as transporters with unanticipated high cycling rates and demonstrate that under cellular conditions ATPases may operate in the kHz-range.

Date: 2025
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DOI: 10.1038/s41467-025-62735-5

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