Park Seung Ju, Park Hoyong, Kim Min-Gyu, Zhang Seungjae, Park Seung Eun, Kim Seyun, Chung ChiHye
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
iScience. 2020 Apr 24;23(4):101000. doi: 10.1016/j.isci.2020.101000. Epub 2020 Mar 22.
The coordination of synaptic vesicle exocytosis and endocytosis supports neurotransmitter release from presynaptic terminals. Although inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (5-IP), are versatile signaling metabolites in many biological events, physiological actions of 5-IP on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP in synaptic transmission in hippocampal brain slices from inositol hexakisphosphate kinase 1 (Ip6k1)-knockout mice. We found that presynaptic release probability was significantly increased in Ip6k1-knockout neurons, implying enhanced activity-dependent synaptic vesicle exocytosis. Expression of wild-type but not catalytically inactive IP6K1 in the Ip6k1-knockout hippocampus restored the altered presynaptic release probability. Moreover, Ip6k1-knockout neurons were insensitive to folimycin, a vacuolar ATPase inhibitor, and dynasore, a dynamin inhibitor, suggesting marked impairment in synaptic endocytosis during exocytosis. Our findings collectively establish that IP6K1 and its product, 5-IP, act as key physiological determinants for inhibition of presynaptic vesicle exocytosis and stimulation of endocytosis at central synapses.
突触小泡胞吐作用和内吞作用的协调支持神经递质从突触前终末释放。尽管肌醇焦磷酸，如5-二磷酸肌醇五磷酸（5-IP），在许多生物事件中是多功能信号代谢物，但5-IP对突触膜小泡运输的生理作用仍不清楚。在这里，我们研究了5-IP在来自肌醇六磷酸激酶1（Ip6k1）基因敲除小鼠的海马脑片中突触传递中的作用。我们发现，Ip6k1基因敲除神经元的突触前释放概率显著增加，这意味着活性依赖的突触小泡胞吐作用增强。在Ip6k1基因敲除的海马体中表达野生型而非催化失活的IP6K1可恢复改变的突触前释放概率。此外，Ip6k1基因敲除神经元对液泡ATP酶抑制剂佛利霉素和发动蛋白抑制剂dynasore不敏感，这表明在胞吐过程中突触内吞作用明显受损。我们的研究结果共同表明，IP6K1及其产物5-IP是抑制突触前小泡胞吐作用和刺激中枢突触内吞作用的关键生理决定因素。
