The role of Synaptobrevin1/VAMP1 in Ca2+-triggered neurotransmitter release at the mouse neuromuscular junction
The role of Synaptobrevin1/VAMP1 in Ca2+-triggered neurotransmitter release at the mouse neuromuscular junction
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DOI：
10.1113/jphysiol.2010.201939
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发表时间：
2011-04-01
影响因子：
5.5
通讯作者：
Lin, Weichun
中科院分区：
文献类型：
--
作者：
Liu, Yun;Sugiura, Yoshie;Lin, Weichun
非技术概述神经肌肉接头（NMJ）是神经和肌肉之间的突触连接。神经肌肉突触传递是高度可靠的，因为每个神经冲动导致释放的神经递质比在肌肉中唤起动作电位所需的更多。这个特征，通常被称为“安全系数”，确保在正常生理条件下，肌肉收缩将响应于每个神经冲动而发生。在这里，我们表明，一个小的，完整的膜蛋白的突触囊泡，命名为synaptobrevin（Syb）/囊泡相关膜蛋白（VAMP），需要在NMJ的最佳突触传递。Syb 1/VAMP 1基因突变可导致小鼠NMJ神经递质释放显著减少，提示Syb 1/VAMP 1在维持NMJ“安全因子”方面具有重要作用。小突触泡蛋白（Synaptobrevin，Syb）/囊泡相关膜蛋白（vesicle-associated membrane protein，VAMP）是突触囊泡的一种小而完整的膜蛋白。Syb 1/VAMP 1和Syb 2/VAMP 2在成年哺乳动物神经元中表现出不同但部分重叠的表达模式：Syb 1主要在脊髓中表达，特别是在神经肌肉接头（NMJ）的运动神经元和运动神经末梢中，而Syb 2主要在脑中的中枢突触中表达。虽然许多研究都集中在Syb 2在大脑中的功能，但很少有研究研究Syb 1的作用。在这里，我们报告，Syb 1在神经肌肉突触传递中起着关键作用。Syb 1的无效突变导致小鼠自发的无义突变，显著损害NMJ的功能，但不损害其结构。特别是，Syb 1突变小鼠的自发和诱发的突触活动相对于对照小鼠显著减少。Syb 1缺陷的NMJ的短期突触可塑性显着改变：成对脉冲促进显着增强，表明突触囊泡的初始释放概率降低。此外，Syb 1缺陷型NMJ在神经递质释放方面表现出明显的抑制作用。这些损害不是由于改变的大小容易释放池的囊泡，但可归因于降低的敏感性和cooperativity钙（Ca 2+）由于缺乏Syb 1。我们的研究结果表明，Syb 1在小鼠NMJ的Ca 2+触发的囊泡胞吐中起着重要的，非冗余的作用。
Non-technical summaryThe neuromuscular junction (NMJ) is the synaptic connection between the nerve and the muscle. The neuromuscular synaptic transmission is highly reliable, as each nerve impulse results in the release of more neurotransmitter than is required for evoking an action potential in the muscle. This feature, often referred as the 'safety factor', ensures that a muscle contraction will occur in response to each nerve impulse under normal physiological conditions. Here we show that a small, integral membrane protein of synaptic vesicles, named synaptobrevin (Syb)/vesicle-associated membrane protein (VAMP), is required for optimum synaptic transmission at the NMJ. A genetic mutation in Syb1/VAMP1 in mice causes marked reduction of neurotransmitter release at the NMJ, suggesting an important role for Syb1/VAMP1 in maintaining the 'safety factor' of the NMJ.Synaptobrevin (Syb)/vesicle-associated membrane protein (VAMP) is a small, integral membrane protein of synaptic vesicles. Two homologous isoforms of synaptobrevin, Syb1/VAMP1 and Syb2/VAMP2, exhibit distinct but partially overlapping patterns of expression in adult mammalian neurons: Syb1 is predominantly expressed in the spinal cord, especially in motor neurons and motor nerve terminals of the neuromuscular junction (NMJ), whereas Syb2 is primarily expressed in central synapses in the brain. Whereas many studies have focused on the function of Syb2 in the brain, few studies have examined the role of Syb1. Here we report that Syb1 plays a critical role in neuromuscular synaptic transmission. A null mutation of Syb1 resulting from a spontaneous, nonsense mutation in mice significantly impairs the function, but not the structure, of the NMJ. In particular, both spontaneous and evoked synaptic activities in Syb1 mutant mice are reduced significantly relative to control mice. Short-term synaptic plasticity in Syb1-deficient NMJs is markedly altered: paired-pulse facilitation is significantly enhanced, suggesting a reduction in the initial release probability of synaptic vesicles. Furthermore, Syb1-deficient NMJs display a pronounced asynchrony in neurotransmitter release. These impairments are not due to an alteration of the size of the readily releasable pool of vesicles, but are attributable to reduced sensitivity and cooperativity to calcium (Ca2+) due to the absence of Syb1. Our findings demonstrate that Syb1 plays an essential, non-redundant role in Ca2+-triggered vesicle exocytosis at the mouse NMJ.