A novel isoform of the secretory pathway Ca²⁺,Mn ²⁺-ATPase, hSPCA2, has unusual properties and is expressed in the brain

Unlike lower eukaryotes, mammalian genomes have a second gene, ATP2C2, encoding a putative member of the family of secretory pathway Ca ²⁺,Mn²⁺-ATPases, SPCA2. Human SPCA2 shares 64% amino acid identity with the protein defective in Hailey Hailey disease, hSPCA1. We show that human SPCA2 (hSPCA2) has a more limited tissue distribution than hSPCA1, with prominent protein expression in brain and testis. In primary neuronal cells, endogenous SPCA2 has a highly punctate distribution that overlaps with vesicles derived from the trans-Golgi network and is thus different from the compact perinuclear distribution of hSPCA1 seen in keratinocytes and nonpolarized cells. Heterologous expression in a yeast strain lacking endogenous Ca²⁺ pumps reveals further functional differences from hSPCA1. Although the Mn²⁺-specific phenotype of hSPCA2 is similar to that of hSPCA1, Ca²⁺ ions are transported with much poorer affinity, resulting in only weak complementation of Ca²⁺-specific yeast phenotypes. These observations suggest that SPCA2 may have a more specialized role in mammalian cells, possibly in cellular detoxification of Mn²⁺ ions, similar to that in yeast. We point to the close links between manganese neurotoxicity and Parkinsonism that would predict an important physiological role for SPCA2 in the brain.