Regulation of uptake and compartmentation of metal ions is important for the maintenance of metal ion homeostasis. To identify mechanisms involved in the protection of plants from Mn toxicity, wild-type yeast was transformed with an Arabidopsis cDNA library and transformants were screened on toxic Mn concentrations. Wild-type yeast could not grow in the presence of 30 mM MnSO 4, while two transformants carrying variants of the same gene were able to grow. Database searches revealed that the isolated cDNAs correspond to AtCAX2, previously described as a vacuolar calcium-proton antiporter. Since no other genes could be identified, AtCAX2 might represent a major function permitting Mn detoxification in this suppressor screen. Furthermore, yeast transformed with the two AtCAX2 cDNAs showed increased sensitivity towards hydrogen peroxide, pointing to a limited availability of cytoplasmic Mn in the presence of AtCAX2 activity. The open reading frames of the cDNA encoded polypeptides that have a 42 and a 92 amino acids shorter N-terminal region relative to the predicted full-length coding region of AtCAX2. In contrast to both truncated cDNAs, the full-length clone was unable to confer Mn resistance to yeast, indicating that, similar to AtCAX1, AtCAX2 also carries an autoinhibitory N-terminal domain regulating the activity of AtCAX2.