Lambert-Eaton syndrome antibodies inhibit acetylcholine release and P/Q-type Ca2+ channels in electric ray nerve endings.
Lambert-Eaton syndrome antibodies inhibit acetylcholine release and P/Q-type Ca2+ channels in electric ray nerve endings.
复制标题
兰伯特-伊顿综合征抗体抑制电射线神经末梢中的乙酰胆碱释放和 P/Q 型 Ca2 通道。
DOI：
10.1111/j.1469-7793.1998.427bq.x
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Kirino,Y
中科院分区：
文献类型：
--
作者：
Satoh,Y;Hirashima,N;Tokumaru,H;Takahashi,MP;Kang,J;Viglione,MP;Kim,YI;Kirino,Y
电压依赖性钙通道（VDCCs）的类型存在于胆碱能末梢分离出的电子器官的射线，日本，的特点是其药理敏感性的基础上，特定的拮抗剂。然后研究来自Lambert-Eaton综合征（LES）患者的自身抗体对这些通道类型的抑制，以确定致病性IgG的特异性。在正常的未处理的突触体制备物中，最大剂量的N-和P和/或Q-型Ca 2+通道拮抗剂ω-芋螺毒素GVIA和ω-agatoxin IVA分别抑制去极化诱发的ACh释放47%和43%。L-型VDCC拮抗剂Calciseptine导致释放减少20%。这表明胞吐释放过程主要由N型和P/Q型VDCC介导。LES IgG或血清引起的抑制ACh释放39-45%，与对照抗体处理的制剂相比。然而，离子霉素诱导的乙酰胆碱释放，并没有改变的抗体。此外，相同的LES抗体抑制牛肾上腺嗜铬细胞的全细胞钙电流（伊卡）。因此，致病性抗体对突触体中存在的VDCC发挥作用。在用LES IgG预处理的制剂中测定三种Ca 2+通道拮抗剂阻断ACh释放的功效。与LES抗体相比，ω-Agatoxin IVA的释放仅额外减少3-5%。尽管用LES IgG预处理，ω-芋螺毒素GVIA和calciseptine抑制释放至接近其对照水平。这些结果表明LES抗体主要下调P/Q型Ca ~（2+）通道，该通道参与电器官胆碱能神经末梢突触前递质的释放。目前的研究结果是一致的假设，即P/Q型VDCCs在神经肌肉接头的LES抗体的目标和抗体的抑制产生的特征性神经肌肉缺陷，这种疾病。
The types of voltage-dependent calcium channels (VDCCs) present in the cholinergic terminals isolated from the electric organ of the ray, Narke japonica, were characterized on the basis of their pharmacological sensitivity to specific antagonists. Inhibition of these channel types by autoantibodies from patients with the Lambert-Eaton syndrome (LES) was then studied to determine the specificity of the pathogenic IgG. In normal untreated synaptosomal preparations, maximal doses of N- and P and/or Q-type Ca2+ channel antagonists, ω-conotoxin GVIA and ω-agatoxin IVA, inhibited depolarization-evoked ACh release by 47% and 43%, respectively. Calciseptine, an L-type VDCC antagonist, caused a 20% reduction in the release. This indicates that the exocytotic release process is predominantly mediated by N- and P/Q-type VDCCs. LES IgG or sera caused an inhibition of ACh release by 39-45% in comparison with the control antibody-treated preparations. The ionomycin-induced ACh release, however, was not altered by the antibodies. Additionally, the same LES antibodies inhibited whole-cell calcium currents (ICa) in bovine adrenal chromaffin cells. Thus, the pathogenic antibodies exert their action on VDCCs present in the synaptosomes. The efficacy of three Ca2+ channel antagonists in blocking ACh release was determined in preparations pretreated with LES IgG. ω-Agatoxin IVA produced only an additional 3-5% reduction in release beyond that obtained with LES antibodies. Despite the pretreatment with LES IgG, ω-conotoxin GVIA and calciseptine inhibited the release to nearly their control levels. These results indicate that LES antibodies mainly downregulate P/Q-type Ca2+ channels which contribute to presynaptic transmitter release from the cholinergic nerve terminals of electric organ. The present findings are consistent with the hypothesis that P/Q-type VDCCs at the neuromuscular junction are the target of LES antibodies and that their inhibition by the antibodies produces the characteristic neuromuscular defect in this disease.