The development of the model animals for, and the analysis of the pathogenic mechanism of Lambert-Eaton myasthenic syndrome

1.阿托品，一种非选择性的mAChR拮抗剂，降低mepp的幅度和频率。通过使用mAChR亚型特异性敲除小鼠，证明M1和M3 mAChR是NMJ释放递质所必需的。我们分析了抗P/Q型Ca通道抗体或来自LEMS患者的抗血清是否减少通道的量或来自HEK 293细胞表面上稳定表达的P/Q型Ca通道的Ca内流。我们成功地制备了抗P/Q型钙通道的抗体，并显示其下调了通道的量。它还减少了去极化依赖性Ca流入。一般认为LEMS是由于NMJ突触前末梢释放Ach的量减少所致。为了验证这一点，我们分析了在存在和不存在K^+通道阻断剂4-氨基吡啶的情况下应用AChE抑制剂E2020的效果。令人惊讶的是，这两种药物的治疗效果不是相加的，而是协同对抗NMJ传播。

1. Atropin, a non-selective mAChR antagonist, reduced both mepp amplitude and frequency. By using mAChR-subtype specific knockout mice, it proved that M1 and M3 mAChR are required for transmitter release at NMJ.2. We analyzed whether anti-P/Q-type Ca channel antibody or antisera from LEMS patients reduce the amount of the channel or the Ca influx from the P/Q-type Ca channels expressed stably on the surface of HEK293 cells. Here we successfully generated anti-P/Q-type Ca channel antibody, and showed mat it down-regulated the amount of the channel. It also reduced depolarization-dependent Ca influx.3. It has been thought that LEMS is caused by the reduction in the amount of Ach released from presynaptic terminals in NMJ. To test this, we analyzed the effects of AChE inhibitor E2020 applied in the presence and the absence of K^+ channel blocker 4-aminopyridine. Surprisingly, the effect of the treatment by both of these drugs were not additive, but synergetic against the NMJ transmission.