title: Regulation of copper transport crossing brain barrier systems by Cu-ATPases: effect of manganese exposure.
abstract: 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.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Xue
authors.initials: X
authors.lastname: Fu
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wendy
authors.initials: W
authors.lastname: Jiang
authors.forename: Andrew Donald
authors.initials: AD
authors.lastname: Monnot
authors.forename: Christopher Alexander
authors.initials: CA
authors.lastname: Bates
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000633:toxicity*; D003300:Copper / Q000134:cerebrospinal fluid* / Q000378:metabolism* / Q000493:pharmacokinetics; D000073840:Copper-Transporting ATPases; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D007150:Immunohistochemistry; D008297:Male; D017895:Manganese Compounds; D018613:Microscopy, Confocal; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013054:Spectrophotometry, Atomic
chemical_list: D027682:Cation Transport Proteins; D002712:Chlorides; D017895:Manganese Compounds; D003300:Copper; D000251:Adenosine Triphosphatases; C486202:Atp7a protein, rat; C550619:Atp7b protein, rat; D000073840:Copper-Transporting ATPases; C025340:manganese chloride; C029892:cupric chloride
keywords: Cu-ATPases; blood-CSF barrier; blood-brain barrier; copper; copper transport; manganese