RGD Reference Report - Regulation of copper transport crossing brain barrier systems by Cu-ATPases: effect of manganese exposure. - Rat Genome Database

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Regulation of copper transport crossing brain barrier systems by Cu-ATPases: effect of manganese exposure.

Authors: Fu, X  Zhang, Y  Jiang, W  Monnot, AD  Bates, CA  Zheng, W 
Citation: Fu X, etal., Toxicol Sci. 2014 Jun;139(2):432-51. doi: 10.1093/toxsci/kfu048. Epub 2014 Mar 10.
RGD ID: 11341682
Pubmed: (View Article at PubMed) PMID:24614235
DOI: Full-text: DOI:10.1093/toxsci/kfu048

Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury.



Gene Ontology Annotations    

Biological Process

Cellular Component

Objects Annotated

Genes (Rattus norvegicus)
Atp7a  (ATPase copper transporting alpha)
Atp7b  (ATPase copper transporting beta)


Additional Information