V-ATPase Membrane Sector Associates with Synaptobrevin to Modulate Neurotransmitter Release
V-ATPase Membrane Sector Associates with Synaptobrevin to Modulate Neurotransmitter Release
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DOI：
10.1016/j.neuron.2010.06.024
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发表时间：
2010-07-29
期刊：
影响因子：
16.2
通讯作者：
El Far, Oussama
中科院分区：
文献类型：
--
作者：
Di Giovanni, Jerome;Boudkkazi, Sami;El Far, Oussama
液泡质子ATP酶对突触囊泡的酸化是神经递质装载所必需的。有争议的研究结果表明，V-ATP酶膜结构域（VO）也有助于通过直接作用于囊泡膜融合的Ca 2+依赖的递质释放，但其潜在的机制仍然不清楚。我们现在报告VO c-亚基和v-SNARE小突触素之间的直接相互作用，构成了V-ATP酶和SNARE介导的融合之间的分子联系。相互作用结构域被映射到VAMP 2的近膜结构域和c亚基的胞质3.4环。急性扰动这种相互作用与c-亚基3.4环肽不影响突触囊泡质子泵的活性，但诱导神经递质释放概率大幅下降，抑制皮质切片和培养的交感神经元，以及胆碱能传递。因此，V-ATP酶可以确保两个独立的功能：质子运输由一个完全组装的V-ATP酶和一个陷阱依赖的VO部门的胞吐作用的作用。
Acidification of synaptic vesicles by the vacuolar proton ATPase is essential for loading with neurotransmitter. Debated findings have suggested that V-ATPase membrane domain (VO) also contributes to Ca2+-dependent transmitter release via a direct role in vesicle membrane fusion, but the underlying mechanisms remain obscure. We now report a direct interaction between VO c-subunit and the v-SNARE synaptobrevin, constituting a molecular link between the V-ATPase and SNARE-mediated fusion. Interaction domains were mapped to the membrane-proximal domain of VAMP2 and the cytosolic 3.4 loop of c-subunit. Acute perturbation of this interaction with c-subunit 3.4 loop peptides did not affect synaptic vesicle proton pump activity, but induced a substantial decrease in neurotransmitter release probability, inhibiting glutamatergic as well as cholinergic transmission in cortical slices and cultured sympathetic neurons, respectively. Thus, V-ATPase may ensure two independent functions: proton transport by a fully assembled V-ATPase and a role in SNARE-dependent exocytosis by the VO sector.