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

• DOI: 10.1007/s00204-017-2031-9
• Publication Date: 2017-07-18T12:06:37Z
• Authors: Mariela S. Ferrei...; Irene C. Mangiala...; Mallku Q. Ontiveros; Debora E. Rinaldi; Jorge Martiarena; Sandra V. Verstra...; Juan Pablo F. C. ...
• Keywords: 0303 health sciences; Erythrocytes; DIVALENT CATION TOXICITY; PLASMA MEMBRANE CALCIUM PUMP; Biological Transport; Phosphatidylserines; ION TRANSPORT; CALCIUM HOMEOSTASIS; Plasma Membrane Calcium-Transporting ATPases; 03 medical and health sciences; HEK293 Cells; Calmodulin; Protein Domains; Metals; https://purl.org/becyt/ford/1.6; Cations; Inactivation, Metabolic; Humans; Calcium; https://purl.org/becyt/ford/1; Cells, Cultured

In the recent years, the toxicity of certain divalent cations has been associated with the alteration of intracellular Ca2+ homeostasis. Among other mechanisms, these cations may affect the functionality of certain Ca2+-binding proteins and/or Ca2+ pumps. The plasma membrane calcium pump (PMCA) maintains Ca2+ 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 (Sr2+, Ba2+, Co2+, Cd2+, Pb2+ or Be2+) could be transported by PMCA. Current results indicate that both purified and intact cell PMCA transported Sr2+ with kinetic parameters close to those of Ca2+ transport. The transport of Pb2+ and Co2+ by purified PMCA was, respectively, 50 and 75% lower than that of Ca2+, but only Co2+ was extruded by intact cells and to a very low extent. In contrast, purified PMCA-but not intact cell PMCA-transported Ba2+ at low rates and only when activated by limited proteolysis or by phosphatidylserine addition. Finally, purified PMCA did not transport Cd2+ or Be2+, although minor Be2+ transport was measured in intact cells. Moreover, Cd2+ impaired the transport of Ca2+ through various mechanisms, suggesting that PMCA may be a potential target of Cd2+-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.