Kϩ 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 ϩ ,K ϩ -ATPase (Na ϩ ,K ϩ -pump) and thereafter induction of a hybrid death of concomitant apoptosis and necrosis. The Na ϩ ,K ϩ -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 2ϩ chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-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 ϩ ,K ϩ -ATPase and an inducer of the hybrid death of central neurons.Aminopyridines, particularly 4-aminopyridine (4-AP), have been investigated as a means of beneficial symptomatic treatment in a variety of neurological conditions of demyelination diseases including multiple sclerosis, myasthenia gravis, and spinal cord injury (Murray and Newsom-Davis, 1981; Jones et al