Effects of tetraethylammonium analogs on apoptosis and membrane currents in cultured cortical neurons

Tetraethylammonium (TEA), the quaternary ammonium ion and nonselective K+ c hannel blocker, is protective against neuronal apoptosis. We now tested two TEA analogs, tetrapentylammonium (TPeA) and tetrahexylammonium (THA), for their effects on apoptotic neuronal death and for their pharmacological pro files on membrane currents in cultured mouse cortical neurons. TPeA and THA (0.1-1.0 muM) attenuated staurosporine-induced caspase-3 activation and ne uronal apoptosis. TPeA and THA blocked the outward delayed rectifier K+ (I- K) current in concentration-dependent manners with IC50 values of 2.7 and 1 .9 muM, respectively. I-K was blocked by TPeA in a use-dependent manner, wh ereas THA blocked I-K regardless of activation state of the channel. TPeA a t 1 muM inhibited the high voltage-activated (HVA) Ca2+ current and the A-t ype K+ current (I-A). TPeA (1-10 mM) also blocked the fast inactivating Na 1 current. The ligand-gated N-methyl-D-aspartate (NMDA) receptor current wa s not affected by up to 20 mM TPeA. THA at 1 muM showed inhibitory effects on I-A, HVA Ca2+, and Na+ currents. THA (10 mM) suppressed NMDA currents. T he data suggest that, as K+ channel blockers and apoptosis antagonists, TPe A and THA are much more potent than TEA; however, they have nonspecific act ions on several voltage-gated or ligand-gated channels.