美国斯坦福大学医学院Christopher Patzke等研究人员发现神经调节质信号双向控制人类突触中的囊泡数目。相关论文于2019年10月3日发表在《细胞》杂志上。
研究人员在人类神经元中发现了一种意料之外的突触前机制，其能够急剧改变突触超微结构并调节突触通讯。神经调节质受体的激活双向控制神经末梢内的突触小泡数目。这种控制与cAMP依赖性蛋白激酶A介导的突触素1磷酸化水平的变化有关。使用条件敲除方法，研究人员揭示了神经调节质诱导的突触小泡数目的控制很大程度上依赖于突触素1。
研究人员提出了一种机制，其中非磷酸化的突触素1“闩锁”突触小泡到活动区的突触前簇。然后，cAMP依赖的突触素1磷酸化去除囊泡。不依赖cAMP的突触素1的去磷酸化反过来募集囊泡。因此，突触素1双向调节突触小泡数目，并修饰突触前神经递质的释放，从而作为人类神经元中神经调节质信号的效应物。
据介绍，神经调节质与突触前和突触后G蛋白偶联受体结合，能够快速改变细胞内cAMP和Ca 2+的水平，并被认为在神经精神病和神经退行性疾病中起重要作用。
附：英文原文
Title: Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses
Author: Christopher Patzke, Marisa M. Brockmann, Jinye Dai, Kathlyn J. Gan, M. Katharina Grauel, Pascal Fenske, Yu Liu, Claudio Acuna, Christian Rosenmund, Thomas C. Südhof
Issue&Volume: 2019/10/03
Abstract: Neuromodulators bind to pre- and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca 2+ levels, and are thought to play important roles in neuropsychiatric and neurodegenerative diseases. Here, we discovered in human neurons an unanticipated presynaptic mechanism that acutely changes synaptic ultrastructure and regulates synaptic communication. Activation of neuromodulator receptors bidirectionally controlled synaptic vesicle numbers within nerve terminals. This control correlated with changes in the levels of cAMP-dependent protein kinase A-mediated phosphorylation of synapsin-1. Using a conditional deletion approach, we reveal that the neuromodulator-induced control of synaptic vesicle numbers was largely dependent on synapsin-1. We propose a mechanism whereby non-phosphorylated synapsin-1 “latches” synaptic vesicles to presynaptic clusters at the active zone. cAMP-dependent phosphorylation of synapsin-1 then removes the vesicles. cAMP-independent dephosphorylation of synapsin-1 in turn recruits vesicles. Synapsin-1 thereby bidirectionally regulates synaptic vesicle numbers and modifies presynaptic neurotransmitter release as an effector of neuromodulator signaling in human neurons.
DOI: 10.1016/j.cell.2019.09.011
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31017-7