Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
Institut für Neurophysiologie, Charité Universitätsmedizin, 10117 Berlin, Germany.
Cell. 2019 Oct 3;179(2):498-513.e22. doi: 10.1016/j.cell.2019.09.011.
Neuromodulators bind to pre- and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca 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.
神经调质与神经递质作用于突触前和突触后 G 蛋白偶联受体 (GPCR)，能够快速改变细胞内环磷酸腺苷 (cAMP) 和 Ca2+水平，被认为在神经精神疾病和神经退行性疾病中发挥重要作用。在这里，我们在人类神经元中发现了一种意想不到的突触前机制，该机制可以快速改变突触超微结构并调节突触通讯。神经调质受体的激活双向控制神经末梢内突触囊泡的数量。这种控制与 cAMP 依赖性蛋白激酶 A 介导的突触结合蛋白-1磷酸化水平的变化相关。通过条件性缺失方法，我们揭示了神经调质诱导的突触囊泡数量的控制在很大程度上依赖于突触结合蛋白-1。我们提出了一种机制，即非磷酸化的突触结合蛋白-1“锁定”突触囊泡到活性区的突触前簇。cAMP 依赖性磷酸化的突触结合蛋白-1随后将囊泡移除。cAMP 非依赖性去磷酸化的突触结合蛋白-1反过来募集囊泡。因此，突触结合蛋白-1作为人类神经元中神经调质信号的效应器，双向调节突触囊泡数量并调节突触前神经递质释放。
