Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels.
Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels.
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DOI：
10.1212/wnl.0000000000001225
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发表时间：
2015-02-10
期刊：
影响因子：
9.9
通讯作者：
Kullmann DM
中科院分区：
文献类型：
--
作者：
Spillane J;Ermolyuk Y;Cano-Jaimez M;Lang B;Vincent A;Volynski KE;Kullmann DM
确定Lambert-Eaton肌无力综合征（LEMS）患者的免疫球蛋白G（IgG）是否减少动作电位诱发的突触囊泡胞吐，以及这种作用是否由P/Q型电压门控钙通道（VGCC）介导。从4例LEMS患者（3例男性，1例女性）（包括2例肺部恶性肿瘤患者）中获得IgG。4例患者均检测到抗P/Q型VGCC抗体，2例检测到抗N型VGCC抗体。我们孵育神经元培养物与LEMS IgG和确定的突触囊泡的总回收池的大小和使用荧光成像的两亲性染料SynaptoRed C1的动作电位诱发的胞吐率。来自健康志愿者的合并IgG用作对照。我们对Cacna 1a基因敲除小鼠缺乏P/Q型钙通道的突触重复了实验，以确定这些通道是否解释了LEMS IgG的致病作用。LEMS IgG对总回收池大小没有影响，但与对照IgG处理的神经元相比，显著降低了野生型神经元中动作电位诱发的突触胞吐的速率。相反，LEMS IgG对缺乏P/Q型通道的神经元中突触囊泡胞吐的速率没有影响。这些数据提供了LEMS IgG通过作用于P/Q型VGCC抑制神经递质释放的直接证据。
To determine whether immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome (LEMS) decreases action potential–evoked synaptic vesicle exocytosis, and whether the effect is mediated by P/Q-type voltage-gated calcium channels (VGCCs). IgG was obtained from 4 patients with LEMS (3 males, 1 female), including 2 patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all 4 patients, and against N-type VGCCs in 2. We incubated neuronal cultures with LEMS IgG and determined the size of the total recycling pool of synaptic vesicles and the rate of action potential–evoked exocytosis using fluorescence imaging of the amphiphilic dye SynaptoRed C1. Pooled IgG from healthy volunteers was used as a control. We repeated the experiments on synapses lacking P/Q-type calcium channels from a Cacna1a knockout mouse to determine whether these channels account for the pathogenic effect of LEMS IgG. LEMS IgG had no effect on the total recycling pool size but significantly reduced the rate of action potential–evoked synaptic exocytosis in wild-type neurons when compared with neurons treated with control IgG. In contrast, LEMS IgG had no effect on the rate of synaptic vesicle exocytosis in neurons lacking P/Q-type channels. These data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.