We report a structural and functional analysis of the PMR2 gene cluster in yeast. We found that several strains of Saccharomyces cerevisiae contain multiple PMR2 genes repeated in tandem, whereas most phylogenetically related yeasts appear to possess only a single PMR2 gene. This unusual tandem array of nearly identical genes encodes putative ion pumps involved in Na+ tolerance. Pmr2a and Pmr2b, the proteins encoded by the first two repeats, differ by only 13 amino acid exchanges. Both proteins share localization to the plasma membrane, but represent distinct isoforms of a putative Na+ pump. When expressed under identical conditions in vivo, Pmr2a and Pmr2b cause different tolerances to Na+ and Li+. Finally, we show that the Na+ tolerance mediated through these pumps is regulated by calmodulin via a calcineurin‐independent mechanism which activates the Pmr2 ion pumps post‐transcriptionally.

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