Ion transport and regulation in a synaptic vesicle glutamate transporter
Ion transport and regulation in a synaptic vesicle glutamate transporter
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DOI：
10.1126/science.aba9202
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发表时间：
2020-05-22
期刊：
影响因子：
56.9
通讯作者：
Stroud, Robert M.
中科院分区：
文献类型：
--
作者：
Li, Fei;Eriksen, Jacob;Stroud, Robert M.
突触囊泡积聚神经递质，通过胞吐作用使量子释放成为突触传递的基础。特定的神经递质转运蛋白负责这种活动，因此对大脑功能至关重要。囊泡谷氨酸转运体（VGLUT）在膜电位的驱动下将主要的兴奋性神经递质谷氨酸浓缩到突触囊泡中。然而，由于缺乏结构信息，人们对它们这样做的机制仍然知之甚少。我们报告了大鼠VGLUT2在3.8埃分辨率下的冷冻电子显微镜结构，并提出了基于结构的低pH和氯化物底物识别和变构激活机制。氯离子的潜在渗透途径与谷氨酸结合位点相交。这些结果证明了VGLUT的活性如何与突触囊泡周期期间质子和氯离子浓度的大位移协调，以确保正常的突触传递。
Synaptic vesicles accumulate neurotransmitters, enabling the quantal release by exocytosis that underlies synaptic transmission. Specific neurotransmitter transporters are responsible for this activity and therefore are essential for brain function. The vesicular glutamate transporters (VGLUTs) concentrate the principal excitatory neurotransmitter glutamate into synaptic vesicles, driven by membrane potential. However, the mechanism by which they do so remains poorly understood owing to a lack of structural information. We report the cryo-electron microscopy structure of rat VGLUT2 at 3.8-angstrom resolution and propose structure-based mechanisms for substrate recognition and allosteric activation by low pH and chloride. A potential permeation pathway for chloride intersects with the glutamate binding site. These results demonstrate how the activity of VGLUTs can be coordinated with large shifts in proton and chloride concentrations during the synaptic vesicle cycle to ensure normal synaptic transmission.