Manganese distribution across the blood-brain barrier. IV. Evidence for brain influx through store-operated calcium channels.
Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood-brain barrier, revealed (54)Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain (54)Mn uptake correlated inversely with calcium (Ca) concentration, but (45)Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as verapamil and amiloride, inhibitors of voltage-operated Ca channels, failed to inhibit Mn uptake into cells. Nickel (Ni), another non-selective inhibitor of several Ca channel types, inhibited Mn and Ca uptake into cells by 88 and 85%, respectively. Cyclopiazonic acid (CPA) and thapsigargin, which activate store-operated calcium channels (SOCCs), increased (54)Mn and (45)Ca uptake into cultured bBMECs. In situ brain perfusion studies were conducted in adult, male Sprague-Dawley rats to verify the cell culture results. Both nickel and verapamil produced a non-significant decrease in Mn and Ca influx. Lanthanum significantly increased Mn influx to 675 and 450% of control in parietal cortex and caudate, respectively, while producing no significant effect on Ca influx. Vanadate, which inhibits Ca-ATPase, inhibited Mn uptake into cultured blood-brain barrier cells, but not into perfused rat brain. Overall these results suggest that both Ca-dependent and Ca-independent mechanisms play a role in brain Mn influx. This work provides evidence that store-operated Ca channels, as well as another mechanism at the blood-brain barrier, likely play a role in carrier-mediated Mn influx into the brain.
Crossgrove
Janelle S
JS
Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536-0305, USA.
Yokel
Robert A
RA
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D002469:Cell Separation; D042783:Endothelial Cells / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008345:Manganese / Q000378:metabolism*; D008670:Metals / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000502:physiology; D013696:Temperature
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008670:Metals; D011506:Proteins; D008345:Manganese; D012964:Sodium; D002118:Calcium