Passive transfer of Lambert-Eaton syndrome to mice induces dihydropyridine sensitivity of neuromuscular transmission
Passive transfer of Lambert-Eaton syndrome to mice induces dihydropyridine sensitivity of neuromuscular transmission
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DOI：
10.1113/jphysiol.2002.021048
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发表时间：
2002-09-01
影响因子：
5.5
通讯作者：
Atchison, WD
中科院分区：
文献类型：
--
作者：
Flink, MT;Atchison, WD
Lambert-Eaton肌无力综合征（LEMS）是一种副肿瘤性疾病，其中自身抗体明显靶向调节运动神经末梢乙酰胆碱（ACh）释放的电压门控Ca 2+通道。P/Q型Ca ~（2+）通道主要参与哺乳动物神经肌肉接头的ACh释放。通过重复给予LEMS患者的血浆将LEMS被动转移至小鼠，降低了神经束膜P/Q型电流的幅度，并在运动神经末梢揭示了二氢吡啶（DHP）敏感的L型Ca 2+电流。本研究旨在确定这种DHP敏感组分是否有助于ACh释放。用来自健康人对照或LEMS患者的血浆处理小鼠30天。对于一些研究，将来自未处理小鼠的横膈膜与LEMS或对照人血浆孵育2或24小时。在膈肌神经肌肉接头处记录终板电位（EPPs）和微型终板电位（MEPPs）。用LEMS等离子体处理小鼠引起LEMS的特征性电生理学体征：在高频刺激下量子含量减少和EPP振幅促进。在与LEMS血浆急性孵育的肌肉中，量子含量也减少。尼莫地平，一个DHP型阻滞剂的L-型钙离子通道，没有显着影响量子含量的肌肉治疗2或24小时，无论是控制或LEMS血浆，或以下慢性治疗与控制血浆。然而，在用LEMS血浆处理30天后，尼莫地平将剩余的量子含量显著降低至尼莫地平前对照水平的57.7 +/-3.3%。因此，DHP-敏感的Ca 2+通道在用LEMS血浆慢性治疗后参与小鼠神经肌肉接头处的突触传递，但不参与急性治疗。然而，即使在很短的时间内暴露于LEMS血浆后，乙酰胆碱的量子释放也会减少。因此，发展的L-型Ca 2+通道的贡献ACh释放在LEMS的被动转移似乎只发生后，量子释放显着受损的持续时间延长，这表明ACh释放装置的适应性反应发生在LEMS。
Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic disorder in which autoantibodies apparently target the voltage-gated Ca2+ channels that regulate acetylcholine (ACh) release at motor nerve terminals. P/Q-type Ca2+ channels are primarily involved in ACh release at mammalian neuromuscular junctions. Passive transfer of LEMS to mice by repeated administration of plasma from LEMS patients reduces the amplitude of the perineurial P/Q-type current, and unmasks a dihydropyridine (DHP)-sensitive L-type Ca2+ current at the motor nerve terminal. The present study sought to determine if this DHP-sensitive component contributes to ACh release. Mice were treated for 30 days with plasma from healthy human controls or patients with LEMS. For some studies, diaphragms from naive mice were incubated with LEMS or control human plasma for 2 or 24 h. End-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) were recorded from neuromuscular junctions in the hemidiaphragm. Treatment of mice with LEMS plasma evoked the characteristic electrophysiological signs of LEMS: reduced quantal content and facilitation of EPP amplitudes at high-frequency stimulation. Quantal content was also reduced in muscles incubated acutely with LEMS plasma. Nimodipine, a DHP-type blocker of L-type Ca2+ channels, did not significantly affect the quantal content of muscles treated for 2 or 24 h with either control or LEMS plasma, or following chronic treatment with control plasma. However, following 30 days treatment with LEMS plasma, nimodipine significantly reduced the remaining quantal content to 57.7 +/- 3.3 % of pre-nimodipine control levels. Thus, DHP-sensitive Ca2+ channels become involved in synaptic transmission at the mouse neuromuscular junction after chronic, but not acute treatment with LEMS plasma. However, reductions in quantal release of ACh occur even after very short periods of exposure to LEMS plasma. As such, development of the L-type Ca2+ channel contribution to ACh release during passive transfer of LEMS appears to occur only after quantal release is significantly impaired for an extended duration, suggesting that an adaptive response of the ACh release apparatus occurs in LEMS.