Trapping channel block of NMDA-activated responses by amantadine and memantine
Trapping channel block of NMDA-activated responses by amantadine and memantine
复制标题
DOI：
10.1152/jn.1997.77.1.309
复制
发表时间：
1997-01-01
影响因子：
2.5
通讯作者：
Johnson, JW
中科院分区：
文献类型：
--
作者：
Blanpied, TA;Boeckman, FA;Johnson, JW
我们研究了抗帕金森病和神经保护剂金刚烷胺和美金刚胺抑制N-甲基-D-天冬氨酸（NMDA）反应的机制。使用培养的大鼠皮质神经元或表达NMDA受体的中国仓鼠卵巢（CHO）细胞进行全细胞记录。金刚烷胺和美金刚都通过结合到通道关闭和激动剂解结合后可以被捕获的位点来阻断NMDA激活的通道。对于神经元受体，金刚烷胺和美金刚胺在-67 mV的IC（50）分别为39和1.4 μ M。当美金刚和激动剂在稳态阻断后被洗掉时，六分之一的阻断通道释放而不是捕获阻断剂;美金刚表现出“部分捕获”。因此，美金刚似乎比苯环利定或（5 R，10 S）-（+）-5-甲基-10，11-二氢-5H-二苯并[1，d]环庚烯-5，10-亚胺（MK-801）具有更小的被捕获倾向。我们接下来研究了可能导致部分捕获的机制。美金刚可被NR 1和NR 2A或NR 2B亚基组成的重组NMDA受体阻断并捕获。在这些受体中，就像在天然受体中一样，药物从六分之一的阻塞通道中释放出来，而不是被困在所有通道中。因此，我们观察到的部分捕获不是由于美金刚胺对培养的皮层神经元中NMDA受体的异质性群体的作用的变化。金刚烷胺和美金刚各自通过在第二个位点以大约低100倍的亲和力结合而非竞争性地抑制NMDA激活的反应，但是这种形式的抑制对美金刚被捕获的程度几乎没有影响。阻断剂作用的一个简单的动力学模型被用来证明，如果通道中美金刚胺的存在影响门控转换或NMDA受体的激动剂亲和力，则可以导致部分捕获。部分捕获保证在存在阻滞剂的突触通信期间，一些通道将在突触响应之间释放阻滞剂。金刚烷胺和美金刚胺在通道阻断后被捕获的程度可能会影响其治疗效果及其对NMDA受体介导的兴奋性突触后电位的调节。
We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl-D-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated channels by binding to a site at which they could be trapped after channel closure and agonist unbinding. For neuronal receptors, the IC(50)s of amantadine and memantine at -67 mV were 39 and 1.4 mu M, respectively. When memantine and agonists were washed off after steady-state block, one-sixth of the blocked channels released rather than trapped the blocker; memantine exhibited ''partial trapping.'' Thus memantine appears to have a lesser tendency to be trapped than do phencyclidine or (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[1,d]cyclihepten-5,10-imine (MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits. In these receptors, as in the native receptors, the drug was released from one-sixth of blocked channels rather than being trapped in all of them. The partial trapping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultured cortical neurons. Amantadine and memantine each noncompetitively inhibited NMDA-activated responses by binding at a second site with roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A simple kinetic model of blocker action was used to demonstrate that partial trapping can result if the presence of memantine in the channel affects the gating transitions or agonist affinity of the NMDA receptor. Partial trapping guarantees that during synaptic communication in the presence of blocker, some channels will release the blocker between synaptic responses. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their modulation of NMDA-receptor-mediated excitatory postsynaptic potentials.