RIM1 confers sustained activity and neurotransmitter vesicle anchring to presynaptic Ca+2 channels
RIM1 confers sustained activity and neurotransmitter vesicle anchring to presynaptic Ca+2 channels
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DOI：
10.1038/nn1904
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发表时间：
2007-06-01
影响因子：
25
通讯作者：
Mori, Yasuo
中科院分区：
文献类型：
--
作者：
Kiyonaka, Shigeki;Wakamori, Minoru;Mori, Yasuo
突触前活动区的分子组织对于由去极化诱导的Ca 2+内流触发的神经递质释放是重要的。在这里，我们展示了一个以前未知的突触前活动区，RIM 1和电压依赖性钙离子通道（VDCCs），控制哺乳动物神经元中的神经递质释放的两个组件之间的相互作用。RIM 1通过其C末端与VDCC β亚基相关，以显著抑制不同神经元VDCC之间的电压依赖性失活。一致的是，在嗜铬细胞瘤神经内分泌PC 12细胞，乙酰胆碱释放显着增强全长和C-末端RIM 1结构，但膜对接囊泡增强只有全长RIM 1。β构建体β-AID显性阴性，其破坏RIM 1-β结合，加速天然VDCC电流的失活，抑制PC 12细胞中的囊泡对接和乙酰胆碱释放，并抑制培养的小脑神经元中的谷氨酸释放。因此，RIM 1与突触前活动区的B的关联支持通过两种不同的机制释放：通过抑制通道失活维持Ca 2+内流，以及在VDCC附近锚定含神经递质的囊泡。
The molecular organization of presynaptic active zones is important for the neurotransmitter release that is triggered by depolarization-induced Ca2+ influx. Here, we demonstrate a previously unknown interaction between two components of the presynaptic active zone, RIM1 and voltage-dependent Ca2+ channels (VDCCs), that controls neurotransmitter release in mammalian neurons. RIM1 associated with VDCC beta-subunits via its C terminus to markedly suppress voltage-dependent inactivation among different neuronal VDCCs. Consistently, in pheochromocytoma neuroendocrine PC12 cells, acetylcholine release was significantly potentiated by the full-length and C-terminal RIM1 constructs, but membrane docking of vesicles was enhanced only by the full-length RIM1. The beta construct beta-AID dominant negative, which disrupts the RIM1-beta association, accelerated the inactivation of native VDCC currents, suppressed vesicle docking and acetylcholine release in PC12 cells, and inhibited glutamate release in cultured cerebellar neurons. Thus, RIM1 association with b in the presynaptic active zone supports release via two distinct mechanisms: sustaining Ca2+ influx through inhibition of channel inactivation, and anchoring neurotransmitter-containing vesicles in the vicinity of VDCCs.