TY - JOUR T1 - Block of Na<sup>+</sup>,K<sup>+</sup>-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 502 LP - 506 DO - 10.1124/jpet.102.045013 VL - 305 IS - 2 AU - Xue Qing Wang AU - Ai Ying Xiao AU - Aizhen Yang AU - Lori LaRose AU - Ling Wei AU - Shan Ping Yu Y1 - 2003/05/01 UR - http://jpet.aspetjournals.org/content/305/2/502.abstract N2 - 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 Ca2+ 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. The American Society for Pharmacology and Experimental Therapeutics ER -