Selectivity of plasma membrane calcium ATPase (PMCA)-mediated extrusion of toxic divalent cations in vitro and in cultured cells

In the recent years, the toxicity of certain divalent cations has been associated with the alteration of intracellular Ca 2+ homeostasis. Among other mechanisms, these cations may affect the functionality of certain Ca 2+ -binding proteins and/or Ca 2+ pumps. The plasma membrane calcium pump (PMCA) maintains Ca 2+ homeostasis in eukaryotic cells by mediating the efflux of this cation in a process coupled to ATP hydrolysis. The aim of this work was to investigate both in vitro and in cultured cells if other divalent cations (Sr 2+ , Ba 2+ , Co 2+ , Cd 2+ , Pb 2+ or Be 2+ ) could be transported by PMCA. Current results indicate that both purified and intact cell PMCA transported Sr 2+ with kinetic parameters close to those of Ca 2+ transport. The transport of Pb 2+ and Co 2+ by purified PMCA was, respectively, 50 and 75% lower than that of Ca 2+ , but only Co 2+ was extruded by intact cells and to a very low extent. In contrast, purified PMCA—but not intact cell PMCA—transported Ba 2+ at low rates and only when activated by limited proteolysis or by phosphatidylserine addition. Finally, purified PMCA did not transport Cd 2+ or Be 2+ , although minor Be 2+ transport was measured in intact cells. Moreover, Cd 2+ impaired the transport of Ca 2+ through various mechanisms, suggesting that PMCA may be a potential target of Cd 2+ -mediated toxicity. The differential capacity of PMCA to transport these divalent cations may have a key role in their detoxification, limiting their noxious effects on cell homeostasis.