Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8266-71. doi: 10.1073/pnas.1219234110. Epub 2013 Apr 30.
Sustained fast neurotransmission requires the rapid replenishment of release-ready synaptic vesicles (SVs) at presynaptic active zones. Although the machineries for exocytic fusion and for subsequent endocytic membrane retrieval have been well characterized, little is known about the mechanisms underlying the rapid recruitment of SVs to release sites. Here we show that the Down syndrome-associated endocytic scaffold protein intersectin 1 is a crucial factor for the recruitment of release-ready SVs. Genetic deletion of intersectin 1 expression or acute interference with intersectin function inhibited the replenishment of release-ready vesicles, resulting in short-term depression, without significantly affecting the rate of endocytic membrane retrieval. Acute perturbation experiments suggest that intersectin-mediated vesicle replenishment involves the association of intersectin with the fissioning enzyme dynamin and with the actin regulatory GTPase CDC42. Our data indicate a role for the endocytic scaffold intersectin in fast neurotransmitter release, which may be of prime importance for information processing in the brain.
持续的神经递质快速释放需要在突触前活性区快速补充准备释放的突触小泡（SVs）。尽管已经很好地描述了胞吐融合和随后的内吞膜回收的机制，但对于 SVs 快速募集到释放位点的机制知之甚少。在这里，我们发现唐氏综合征相关的内吞支架蛋白 intersectin 1 是募集准备释放的 SVs 的关键因素。截短 intersectin 1 的表达或急性干扰 intersectin 的功能会抑制准备释放的 SVs 的补充，导致短期抑郁，而不会显著影响内吞膜回收的速度。急性扰动实验表明，intersectin 介导的囊泡补充涉及 intersectin 与分裂酶 dynamin 和肌动蛋白调节 GTPase CDC42 的结合。我们的数据表明内吞支架 intersectin 在快速神经递质释放中起作用，这对于大脑中的信息处理可能至关重要。
