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 Ca2+,Mn(2+)-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 Mn(2+)-specific phenotype of hSPCA2 is similar to that of hSPCA1, Ca2+ ions are transported with much poorer affinity, resulting in only weak complementation of Ca(2+)-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.
Xiang
Minghui
M
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Mohamalawari
Deepti
D
Rao
Rajini
R
D000595:Amino Acid Sequence; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D006056:Golgi Apparatus / Q000737:chemistry; D006801:Humans; D008658:Inactivation, Metabolic; D008345:Manganese / Q000378:metabolism; D008969:Molecular Sequence Data
D008345:Manganese; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium