ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine--hydroxylase

Katharina Schmidt, Martina Ralle, Thomas Schaffer, Samuel Jayakanthan, Bilal Bari, Abigael Muchenditsi, Svetlana Lutsenko

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The copper (Cu) transporters ATPase copper-transporting alpha (ATP7A) and ATPase copper-transporting beta (ATP7B) are essential for the normal function of the mammalian central nervous system. Inactivation of ATP7A or ATP7B causes the severe neurological disorders, Menkes disease and Wilson disease, respectively. In both diseases, Cu imbalance is associated with abnormal levels of the catecholamine-type neurotransmitters dopamine and norepinephrine. Dopamine is converted to norepinephrine by dopamine--hydroxylase (DBH), which acquires its essential Cu cofactor from ATP7A. However, the role of ATP7B in catecholamine homeostasis is unclear. Here, using immunostaining of mouse brain sections and cultured cells, we show that DBH-containing neurons express both ATP7A and ATP7B. The two transporters are located in distinct cellular compartments and oppositely regulate the export of soluble DBH from cultured neuronal cells under resting conditions. Down-regulation of ATP7A, overexpression of ATP7B, and pharmacological Cu depletion increased DBH retention in cells. In contrast, ATP7B inactivation elevated extracellular DBH. Proteolytic processing and the specific activity of exported DBH were not affected by changes in ATP7B levels. These results establish distinct regulatory roles for ATP7A and ATP7B in neuronal cells and explain, in part, the lack of functional compensation between these two transporters in human disorders of Cu imbalance.

Original languageEnglish (US)
Pages (from-to)20085-20098
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number52
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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