Received for publication October 8, 2002.
Revised October 30, 2002.
Accepted for publication December 9, 2002.

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 be a 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 mM range. At similar concentrations, 4-AP induced a neuronal death sensitive to attenuations by the caspase inhibitor Z-VAD-FMK or Ca²⁺ chelator BAPTA-AM. 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.

Key words: Apoptosis, Calcium, Na+ pump, Necrosis, Potassium channel blocker, TEA