Heterodimerization of Munc13 C(2)A domain with RIM regulates synaptic vesicle docking and priming.
Heterodimerization of Munc13 C(2)A domain with RIM regulates synaptic vesicle docking and priming.
复制标题
DOI：
10.1038/ncomms15293
复制
发表时间：
2017-05-10
影响因子：
16.6
通讯作者：
Rosenmund C
中科院分区：
文献类型：
--
作者：
Camacho M;Basu J;Trimbuch T;Chang S;Pulido-Lozano C;Chang SS;Duluvova I;Abo-Rady M;Rizo J;Rosenmund C
突触前活性区蛋白Munc 13是神经递质释放所必需的，在囊泡对接和启动中起关键作用。从机制上讲，认为Munc 13的C2 A结构域通过同源二聚化抑制引发功能，并且RIM破坏了形成单体引发活性Munc 13的自身抑制性同源二聚化。然而，目前尚不清楚C2 A结构域是否介导除了这种失活-激活开关以外的其他Munc 13功能。在这里，我们利用突变，调节同源二聚化和异源二聚化状态，以确定额外的Munc 13 C2 A结构域的作用。使用电子显微镜和电生理学在海马培养，我们表明，C2 A域是至关重要的囊泡释放的额外步骤，包括囊泡对接。只有当Munc 13通过其C2 A结构域与RIM异源二聚化时，最佳的囊泡对接和引发才是可能的。除了作为一个开关模块，我们的数据表明，Munc 13-RIM异二聚体是一个积极的组成部分的囊泡对接，引发和释放复合物。RIM和Munc 13的C2 A结构域之间的相互作用是突触囊泡引发所必需的。在这里，作者展示了Munc 13的C2 A结构域的新含义，通过其与RIM的动态相互作用，在编排广泛的调制操作，形状囊泡对接，启动和神经递质释放。
The presynaptic active zone protein Munc13 is essential for neurotransmitter release, playing key roles in vesicle docking and priming. Mechanistically, it is thought that the C2A domain of Munc13 inhibits the priming function by homodimerization, and that RIM disrupts the autoinhibitory homodimerization forming monomeric priming-competent Munc13. However, it is unclear whether the C2A domain mediates other Munc13 functions in addition to this inactivation–activation switch. Here, we utilize mutations that modulate the homodimerization and heterodimerization states to define additional roles of the Munc13 C2A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C2A domain is critical for additional steps of vesicular release, including vesicle docking. Optimal vesicle docking and priming is only possible when Munc13 heterodimerizes with RIM via its C2A domain. Beyond being a switching module, our data suggest that the Munc13-RIM heterodimer is an active component of the vesicle docking, priming and release complex. The interaction between RIM and the C2A domain of Munc13 is known to be required for synaptic vesicle priming. Here the authors show new implications of the C2A domain of Munc13, through its dynamic interaction with RIM, in orchestrating a wide range of modulatory operations that shape vesicle docking, priming and neurotransmitter release.