Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels.
Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels.
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神经肌肉传导抑制会导致缺乏 BK 钾通道的小鼠虚弱。
DOI：
10.1085/jgp.201912526
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Rich,MarkM
中科院分区：
文献类型：
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作者：
Wang,Xueyong;Burke,StevenRA;Talmadge,RobertJ;Voss,AndrewA;Rich,MarkM
缺乏功能性大电导电压和Ca2+激活的K+通道（BK通道）的小鼠是可行的，但有运动缺陷，包括共济失调和虚弱。虚弱的原因尚不清楚。在这项研究中，我们在体内发现，缺乏BK通道（BK−/−）的小鼠骨骼肌对神经刺激的反应较弱，但对直接肌肉刺激的反应不强，这表明神经肌肉传递失败。BK−/−神经肌肉接点（NMJ）的电压钳研究显示，与WT幼崽相比，诱发终板电流幅度和自发囊泡释放频率降低。对50 hz刺激的反应表明，BK−/−小鼠囊泡释放的可能性降低，提示突触前Ca2+进入降低。在WT NMJs中，BK通道的药理阻断不会影响NMJ功能，令人惊讶的是，BK−/−NMJs中囊泡释放的减少不是由于BK通道介导的K+电流的损失。对我们数据的可能解释包括BK通道对NMJ发育的影响，BK通道在调节突触前Ca2+电流中的作用或Ca2+在触发释放中的有效性。与Ca2+进入减少或Ca2+触发释放的有效性一致，在BK−/−小鼠中，使用3,4-二氨基吡啶将动作电位的正常化诱发释放扩大到WT水平。腹腔注射3,4-二氨基吡啶完全恢复BK - / -小鼠体内神经刺激的肌肉力量。我们的工作表明，缺乏BK通道的小鼠由于NMJ的囊泡释放缺陷而具有弱点。
Mice lacking functional large-conductance voltage- and Ca2+-activated K+channels (BK channels) are viable but have motor deficits including ataxia and weakness. The cause of weakness is unknown. In this study, we discovered, in vivo, that skeletal muscle in mice lacking BK channels (BK−/−) was weak in response to nerve stimulation but not to direct muscle stimulation, suggesting a failure of neuromuscular transmission. Voltage-clamp studies of the BK−/−neuromuscular junction (NMJ) revealed a reduction in evoked endplate current amplitude and the frequency of spontaneous vesicle release compared with WT littermates. Responses to 50-Hz stimulation indicated a reduced probability of vesicle release in BK−/−mice, suggestive of lower presynaptic Ca2+entry. Pharmacological block of BK channels in WT NMJs did not affect NMJ function, surprisingly suggesting that the reduced vesicle release in BK−/−NMJs was not due to loss of BK channel–mediated K+current. Possible explanations for our data include an effect of BK channels on development of the NMJ, a role for BK channels in regulating presynaptic Ca2+current or the effectiveness of Ca2+in triggering release. Consistent with reduced Ca2+entry or effectiveness of Ca2+in triggering release, use of 3,4-diaminopyridine to widen action potentials normalized evoked release in BK−/−mice to WT levels. Intraperitoneal application of 3,4-diaminopyridine fully restored in vivo nerve-stimulated muscle force in BK−/−mice. Our work demonstrates that mice lacking BK channels have weakness due to a defect in vesicle release at the NMJ.