Plasma membrane Ca ATPase 1 (PMCA1) but not PMCA4 is critical for B-cell development and Ca homeostasis in mice.

The amplitude and duration of Ca signaling is crucial for B-cell development and self-tolerance; however, the mechanisms for terminating Ca signals in B cells have not been determined. In lymphocytes, plasma membrane Ca ATPase (PMCA) isoforms 1 and 4 (PMCA1 and PMCA4, aka ATP2B1 and ATP2B4) are the main candidates for expelling Ca from the cell through the plasma membrane. We report here that Pmca4 (Atp2b4) KO mice had normal B-cell development, while mice with a conditional KO of Pmca1 (Atp2b1) had greatly reduced numbers of B cells, particularly splenic follicular B cells, marginal zone B cells, and peritoneal B-1a cells. Mouse and naïve human B cells showed only PMCA1 expression and no PMCA4 by western blot, in contrast to T cells, which did express PMCA4. Calcium handling was normal in Pmca4 B cells, but Pmca1 KO B cells had elevated basal levels of Ca , elevated levels in ER stores, and reduced Ca clearance. These findings show that the PMCA1 isoform alone is required to ensure normal B-cell Ca signaling and development, which may have implications for therapeutic targeting of PMCAs and Ca in B cells.