Wang X, Xiao A Y, Ichinose T, Yu S P
Department of Neurology, Center for the Study of Nervous System Injury, School of Medicine, Washington University, St. Louis, Missouri 63110, USA.
J Pharmacol Exp Ther. 2000 Nov;295(2):524-30.
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.
四乙铵（TEA），一种季铵离子和非选择性钾（K⁺）通道阻滞剂，对神经元凋亡具有保护作用。我们现在测试了两种TEA类似物，四戊铵（TPeA）和四己铵（THA），观察它们对凋亡性神经元死亡的影响以及对培养的小鼠皮质神经元膜电流的药理学特性。TPeA和THA（0.1 - 1.0微摩尔）减弱了星形孢菌素诱导的半胱天冬酶-3激活和神经元凋亡。TPeA和THA以浓度依赖性方式阻断外向延迟整流钾（I(K)）电流，IC(50)值分别为2.7和1.9微摩尔。TPeA以使用依赖性方式阻断I(K)，而THA无论通道的激活状态如何都能阻断I(K)。1微摩尔的TPeA抑制高电压激活（HVA）钙（Ca²⁺）电流和A型钾（I(A)）电流。TPeA（1 - 10微摩尔）也阻断快速失活的钠（Na⁺）电流。高达20微摩尔的TPeA对配体门控N-甲基-D-天冬氨酸（NMDA）受体电流没有影响。1微摩尔的THA对I(A)、HVA Ca²⁺和Na⁺电流有抑制作用。10微摩尔的THA抑制NMDA电流。数据表明，作为K⁺通道阻滞剂和凋亡拮抗剂，TPeA和THA比TEA更有效；然而，它们对几种电压门控或配体门控通道具有非特异性作用。
