title: Block of Na+,K+-ATPase and induction of hybrid death by 4-aminopyridine in cultured cortical neurons.
abstract: K(+) channel blockers such as 4-aminopyridine (4-AP) can be toxic to neurons; the cellular mechanism underlying the toxicity, however, is obscure. In cultured mouse cortical neurons, we tested the hypothesis that the toxic effect of 4-AP might result from inhibiting the Na(+),K(+)-ATPase (Na(+),K(+)-pump) and thereafter induction of a hybrid death of concomitant apoptosis and necrosis. The Na(+),K(+)-pump activity, monitored as whole-cell membrane currents, was markedly blocked by 4-AP in concentration- and voltage-dependent manners in low millimolar ranges. At similar concentrations, 4-AP induced a neuronal death sensitive to attenuation by the caspase inhibitor Z-VAD-FMK (Z-Val-Ala-Asp(OMe)-fluoromethyl ketone) or Ca(2+) chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester). Electron microscopy confirmed hybrid ultrastructural features of coexisting apoptotic and necrotic components in same cells. We suggest that 4-AP is a potent antagonist of the Na(+),K(+)-ATPase and an inducer of the hybrid death of central neurons.
authors.affiliation: Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Xue Qing
authors.initials: XQ
authors.lastname: Wang
authors.forename: Ai Ying
authors.initials: AY
authors.lastname: Xiao
authors.forename: Aizhen
authors.initials: A
authors.lastname: Yang
authors.forename: Lori
authors.initials: L
authors.lastname: LaRose
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006822:Hybrid Cells / Q000187:drug effects; D051379:Mice; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013327:Strophanthidin / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D013757:Tetraethylammonium Compounds; D013327:Strophanthidin; D015761:4-Aminopyridine; D000254:Sodium-Potassium-Exchanging ATPase