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J. Biol. Chem., Vol. 280, Issue 12, 11608-11614, March 25, 2005

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A Novel Isoform of the Secretory Pathway Ca²⁺,Mn²⁺-ATPase, hSPCA2, Has Unusual Properties and Is Expressed in the Brain^*

Minghui Xiang, Deepti Mohamalawari, and Rajini Rao

From the Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Unlike lower eukaryotes, mammalian genomes have a second gene, ATP2C2, encoding a putative member of the family of secretory pathway Ca²⁺,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.

Received for publication, November 19, 2004 , and in revised form, January 21, 2005.

^* This work was supported by National Institutes of Health Grant GM62142 and a grant-in-aid from the American Heart Association Mid-Atlantic affiliate (to R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-955-4732; Fax: 410-955-0461; E-mail: rrao{at}jhmi.edu.

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