Abstract

Tetraethylammonium (TEA), the quaternary ammonium ion and nonselective K⁺ channel 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 profiles on membrane currents in cultured mouse cortical neurons. TPeA and THA (0.1–1.0 μM) attenuated staurosporine-induced caspase-3 activation and neuronal 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 μM, respectively. I_K was blocked by TPeA in a use-dependent manner, whereas THA blockedI_K regardless of activation state of the channel. TPeA at 1 μM inhibited the high voltage-activated (HVA) Ca²⁺ current and the A-type K⁺ current (I_A). TPeA (1–10 μM) also blocked the fast inactivating Na⁺ current. The ligand-gatedN-methyl-d-aspartate (NMDA) receptor current was not affected by up to 20 μM TPeA. THA at 1 μM showed inhibitory effects on I_A, HVA Ca²⁺, and Na⁺ currents. THA (10 μM) suppressed NMDA currents. The data suggest that, as K⁺ channel blockers and apoptosis antagonists, TPeA and THA are much more potent than TEA; however, they have nonspecific actions on several voltage-gated or ligand-gated channels.