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

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 microM) 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 IC(50) values of 2.7 and 1.9 microM, respectively. I(K) was blocked by TPeA in a use-dependent manner, whereas THA blocked I(K) regardless of activation state of the channel. TPeA at 1 microM inhibited the high voltage-activated (HVA) Ca(2+) current and the A-type K(+) current (I(A)). TPeA (1-10 microM) also blocked the fast inactivating Na(+) current. The ligand-gated N-methyl-D-aspartate (NMDA) receptor current was not affected by up to 20 microM TPeA. THA at 1 microM showed inhibitory effects on I(A), HVA Ca(2+), and Na(+) currents. THA (10 microM) 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.