title: Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin.
abstract: Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O(2), 4h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca(2+) currents were acquired immediately after hypoxic exposure or after 48h recovery in 95% air/5% CO(2). Maximal Ca(2+) current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca(2+) currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca(2+) currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca(2+) for calcineurin activation, as nimodipine during hypoxia prevented post-hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation.
authors.affiliation: Department of Neurology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiang
authors.forename: Damien
authors.initials: D
authors.lastname: Earl
authors.forename: Trisha
authors.initials: T
authors.lastname: Dwyer
authors.forename: Brian L
authors.initials: BL
authors.lastname: Behrle
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Tietz
authors.forename: L John
authors.initials: LJ
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D020746:Calcium Channels, L-Type / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D020746:Calcium Channels, L-Type; D019703:Calcineurin; D016559:Tacrolimus