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 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.
Footnotes
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This work was supported by grants from the National Science Foundation (9817151 to S.P.Y.), American Heart Association and Burgher Foundation (0170063N to W.L, and 0170064N to S.P.Y), and the National Institutes of Health (NS42236 to S.P.Y. and NS37337 to W.L.).
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DOI: 10.1124/jpet.102.045013
- Abbreviations:
- 4-AP
- 4-aminopyridine
- AM
- acetoxymethyl ester
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- HS
- horse serum
- LDH
- lactate dehydrogenase
- MEM
- minimal essential medium
- MK-801
- (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- NMDA
- N-methyl-d-aspartate
- TEA
- tetraethylammonium
- Z-VAD-FMK
- Z-Val-Ala-Asp(OMe)-fluoromethyl ketone
- Received October 1, 2002.
- Accepted December 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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