New insights into the Ca2+-ATPases that contribute to cadmium tolerance in yeast

Cadmium (Cd²⁺) is a toxic heavy metal which triggers several toxic effects in eukaryotes, including neurotoxicity and impaired calcium metabolism. In the model organism Saccharomyces cerevisiae, the best characterized pathway for Cd²⁺ detoxification involves conjugation with glutathione (GSH) and subsequent transport to vacuoles by Ycf1p, an ATPase homologous to human MRP1 (Multidrug resistance associated protein 1). However, Cd²⁺ tolerance also can be mediated by Pmr1p, a Ca²⁺ pump located in the Golgi membrane, possibly through to the secretory pathway. Herein, we showed that inactivation of the PMR1 gene, alone or simultaneously with YCF1, delayed initial Cd²⁺ capture compared to wild-type (WT) cells. In addition, Cd²⁺ treatment altered the expression profile of yeast internal Ca²⁺ transporters; specifically, PMC1 gene expression is induced substantially by the metal in WT cells, and this induction is stronger in mutants lacking YCF1. Taken together, these results indicate that, in addition to Pmr1p, the vacuolar Ca²⁺-ATPase Pmc1p also helps yeast cells cope with Cd²⁺ toxicity. We propose a model where Pmc1p and Pmr1p Ca²⁺-ATPase function in cooperation with Ycf1p to promote Cd²⁺ detoxification.