Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nat Neurosci. 2012 Mar 11;15(5):738-45. doi: 10.1038/nn.3067.
Synaptic vesicles in the brain harbor several soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins. With the exception of synaptobrevin2, or VAMP2 (syb2), which is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here we show that in mice syb2 drives rapid Ca(2+)-dependent synchronous neurotransmission, whereas the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca(2+)-dependent asynchronous release. At inhibitory nerve terminals, up- or downregulation of VAMP4 causes a correlated change in asynchronous release. Biochemically, VAMP4 forms a stable complex with SNAREs syntaxin-1 and SNAP-25 that does not interact with complexins or synaptotagmin-1, proteins essential for synchronous neurotransmission. Optical imaging of individual synapses indicates that trafficking of VAMP4 and syb2 show minimal overlap. Taken together, these findings suggest that VAMP4 and syb2 diverge functionally, traffic independently and support distinct forms of neurotransmission. These results provide molecular insight into how synapses diversify their release properties by taking advantage of distinct synaptic vesicle-associated SNAREs.
在大脑中，突触小泡内含有几种可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白。除了直接参与囊泡融合的突触融合蛋白 2，或 VAMP2（syb2）外，这些 SNARE 在神经递质传递中的作用尚不清楚。在这里，我们展示了在小鼠中，syb2 驱动快速 Ca2+依赖性同步神经递质传递，而结构同源的 SNARE 蛋白 VAMP4 选择性地维持大 Ca2+依赖性异步释放。在抑制性神经末梢，VAMP4 的上调或下调会导致异步释放发生相关变化。从生物化学角度来看，VAMP4 与 SNAREs 突触融合蛋白 1 和 SNAP-25 形成稳定的复合物，而与对于同步神经递质传递至关重要的复合蛋白或突触结合蛋白 1 不相互作用。对单个突触的光学成像表明，VAMP4 和 syb2 的运输几乎没有重叠。总之，这些发现表明，VAMP4 和 syb2 在功能上存在差异，运输方式独立，并支持不同形式的神经递质传递。这些结果为我们提供了分子层面的认识，即突触如何通过利用不同的突触小泡相关 SNARE 来多样化其释放特性。
