Bowie D, Lange G D, Mayer M L
Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 1998 Oct 15;18(20):8175-85. doi: 10.1523/JNEUROSCI.18-20-08175.1998.
The mechanisms by which polyamines block AMPA and kainate receptors are not well understood, but it has been generally assumed that they act as open-channel blockers. Consistent with this, voltage-jump relaxation analysis of GluR6 equilibrium responses to domoate could be well fit, assuming that spermine, spermidine, and philanthotoxin are weakly permeable open-channel blockers. Analysis of rate constants for binding and dissociation of polyamines indicated that the voltage dependence of block arose primarily from changes in koff rather than kon. Experiments with changes in Na concentration further indicate that the voltage dependence of polyamine block was governed by ion flux via open channels. However, responses to 1 msec applications of L-Glu revealed slow voltage-dependent rise-times, suggesting that polyamines additionally bind to closed states. A kinetic model, which included closed-channel block, reproduced these observations but required that polyamines accelerate channel closure either through an allosteric mechanism or by emptying the pore of permeant ions. Simulations with this model reveal that polyamine block confers novel activity-dependent regulation on calcium-permeable AMPA and kainate receptor responses.
多胺阻断AMPA和海人藻酸受体的机制尚未完全明确，但一般认为它们作为开放通道阻断剂发挥作用。与此一致的是，假设精胺、亚精胺和 philanthotoxin 是弱渗透性的开放通道阻断剂，对海人藻酸的GluR6平衡反应进行电压跃变弛豫分析能够得到很好的拟合。对多胺结合和解离速率常数的分析表明，阻断的电压依赖性主要源于解离速率常数（koff）的变化，而非结合速率常数（kon）的变化。改变钠离子浓度的实验进一步表明，多胺阻断的电压依赖性受通过开放通道的离子通量控制。然而，对1毫秒L-谷氨酸应用的反应显示出缓慢的电压依赖性上升时间，这表明多胺还能与关闭状态结合。一个包含关闭通道阻断的动力学模型重现了这些观察结果，但要求多胺通过变构机制或通过排空通透离子的孔道来加速通道关闭。用该模型进行的模拟表明，多胺阻断赋予了钙通透性AMPA和海人藻酸受体反应新的活性依赖性调节。
