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

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

doi:10.1074/jbc.RA118.004889

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

Journal Article · Fri Oct 19 00:00:00 EDT 2018 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA118.004889· OSTI ID:1600788

Schmidt, Katharina ^[1]; Ralle, Martina ^[2]; Schaffer, Thomas ^[1]; Jayakanthan, Samuel ^[1]; Bari, Bilal ^[1]; Muchenditsi, Abigael ^[1];

^[1]

Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
Oregon Health and Science Univ., Portland, OR (United States)

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-β-hydroxylase (DBH), which acquires its essential Cu cofactor from ATP7A. However, the role of ATP7B in catecholamine homeostasis is unclear. In this work, 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: 2R01GM101502; AC02-06CH11357

OSTI ID:: 1600788

Journal Information:: Journal of Biological Chemistry, Vol. 293, Issue 52; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
copper transport
vesicles
dopamine-β-hydroxylase
cellular regulation
intracellular trafficking
ATP7A
ATP7B
SH-SY5Y cells
noradrenergic
locus coeruleus
constitutive secretion
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Title: ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase

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