Department of Functional Genomics, CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Center, Amsterdam, 1081 HV, Netherlands.
Science. 2010 Mar 26;327(5973):1614-8. doi: 10.1126/science.1183765. Epub 2010 Feb 11.
Synaptic vesicle fusion in brain synapses occurs in phases that are either tightly coupled to action potentials (synchronous), immediately following action potentials (asynchronous), or as stochastic events in the absence of action potentials (spontaneous). Synaptotagmin-1, -2, and -9 are vesicle-associated Ca2+ sensors for synchronous release. Here we found that double C2 domain (Doc2) proteins act as Ca2+ sensors to trigger spontaneous release. Although Doc2 proteins are cytosolic, they function analogously to synaptotagmin-1 but with a higher Ca2+ sensitivity. Doc2 proteins bound to N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complexes in competition with synaptotagmin-1. Thus, different classes of multiple C2 domain-containing molecules trigger synchronous versus spontaneous fusion, which suggests a general mechanism for synaptic vesicle fusion triggered by the combined actions of SNAREs and multiple C2 domain-containing proteins.
脑突触中的突触囊泡融合发生在与动作电位紧密偶联的阶段（同步）、紧随动作电位之后（异步），或者在没有动作电位的情况下作为随机事件发生（自发）。突触融合蛋白-1、-2 和 -9 是同步释放的囊泡相关 Ca2+ 传感器。在这里，我们发现双 C2 结构域（Doc2）蛋白作为 Ca2+ 传感器触发自发释放。尽管 Doc2 蛋白位于细胞质中，但它们的功能类似于突触融合蛋白-1，但具有更高的 Ca2+ 敏感性。Doc2 蛋白与 N-乙基马来酰亚胺敏感因子附着受体（SNARE）复合物结合，与突触融合蛋白-1 竞争。因此，不同类别的含有多个 C2 结构域的分子触发同步与自发融合，这表明 SNARE 和多个含有 C2 结构域的蛋白共同作用触发突触囊泡融合的一般机制。
