Neuroplastin and Basigin are essential auyiliary subunits of plasma membrane Ca2+-ATPases and key regulators of Ca2+ clearance

Plasma membrane Ca²⁺-ATPases (PMCAs), a family of P-type ATPases, extrude Ca²⁺ ions from the cytosol to the extracellular space and are considered to be key regulators of Ca²⁺ signaling. Here we show by functional proteomics that native PMCAs are heteromeric complexes that are assembled from two pore-forming PMCA1-4 subunits and two of the single-span membrane proteins, either neuroplastin or basigin. Contribution of the two Ig domain-containing proteins varies among different types of cells and along postnatal development. Complex formation of neuroplastin or basigin with PMCAs1-4 occurs in the endoplasmic reticulum and is obligatory for stability of the PMCA proteins and for delivery of PMCA complexes to the surface membrane. Knockout and (over)-expression of both neuroplastin and basigin profoundly affect the time course of PMCA-mediated Ca²⁺ transport, as well as submembraneous Ca²⁺ concentrations under steady-state conditions. Together, these results establish neuroplastin and basigin as obligatory auxiliary subunits of native PMCAs and key regulators of intracellular Ca²⁺ concentration.