Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

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• 作者：Kun Xiang^a ; ^b ; ¹ ; Damien Earl^b ; Trisha Dwyer^a ; Brian L. Behrle^a ; ^b ; ^c ; Elizabeth I. Tietz^b ; L. John Greenfield Jr.^a ; ^b ; ^c ; ^{ljgreenfield@uams.edu}
• 关键词：AKAP ; protein kinase A anchoring protein ; CsA ; cyclosporine A ; DIV ; days in vitro ; dH2O ; distilled water ; FUDR ; 5-fluoro-2&prime ; -deoxyuridine ; FK-506 ; tacrolimus ; GABAAR ; GABA type A receptor ; HIF-1伪 ; hypoxia-inducible factor 1 alpha ; HS ; horse serum ; H
• 刊名：Epilepsy Research
• 出版年：2012
• 期刊代码：87_09201211
• 类别：med
• 出版时间：May, 2012
• 卷：99
• 期：3
• 页码：293-305
• 文件大小：1297 K

摘要

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Summary

Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1%O₂, 4 h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca²⁺ currents were acquired immediately after hypoxic exposure or after 48 h recovery in 95%air/5%CO₂. Maximal Ca²⁺ current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48 h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca²⁺ 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 Ca²⁺ currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca²⁺ 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.