Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Department of Clinical Genetics, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2021 May 4;118(18). doi: 10.1073/pnas.2012137118.
Neuropeptides and neurotrophic factors secreted from dense core vesicles (DCVs) control many brain functions, but the calcium sensors that trigger their secretion remain unknown. Here, we show that in mouse hippocampal neurons, DCV fusion is strongly and equally reduced in synaptotagmin-1 (Syt1)- or Syt7-deficient neurons, but combined Syt1/Syt7 deficiency did not reduce fusion further. Cross-rescue, expression of Syt1 in Syt7-deficient neurons, or vice versa, completely restored fusion. Hence, both sensors are rate limiting, operating in a single pathway. Overexpression of either sensor in wild-type neurons confirmed this and increased fusion. Syt1 traveled with DCVs and was present on fusing DCVs, but Syt7 supported fusion largely from other locations. Finally, the duration of single DCV fusion events was reduced in Syt1-deficient but not Syt7-deficient neurons. In conclusion, two functionally redundant calcium sensors drive neuromodulator secretion in an expression-dependent manner. In addition, Syt1 has a unique role in regulating fusion pore duration.
从致密核心囊泡 (DCV) 中分泌的神经肽和神经营养因子控制着许多大脑功能，但触发它们分泌的钙传感器仍然未知。在这里，我们表明在小鼠海马神经元中，突触结合蛋白-1 (Syt1) 或 Syt7 缺陷神经元中的 DCV 融合明显且相等地减少，但 Syt1/Syt7 联合缺陷并没有进一步减少融合。交叉拯救，Syt1 在 Syt7 缺陷神经元中的表达，或反之亦然，完全恢复了融合。因此，这两种传感器都是限速的，在单一途径中起作用。在野生型神经元中过度表达任一种传感器都证实了这一点，并增加了融合。Syt1 与 DCV 一起运输，并存在于融合的 DCV 上，但 Syt7 主要从其他位置支持融合。最后，在 Syt1 缺陷型神经元中，单个 DCV 融合事件的持续时间缩短，但在 Syt7 缺陷型神经元中则不然。总之，两种功能上冗余的钙传感器以表达依赖性的方式驱动神经调质的分泌。此外，Syt1 在调节融合孔持续时间方面具有独特的作用。
