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Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission.
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-03-22 , DOI: 10.15252/embj.2021109352
Guan-Ting Liu 1 , Gaga Kochlamazashvili 1 , Dmytro Puchkov 1 , Rainer Müller 2 , Carsten Schultz 2, 3 , Albert I Mackintosh 1 , Dennis Vollweiter 1 , Volker Haucke 1, 4, 5 , Tolga Soykan 1
Affiliation  

Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly understood at the molecular level. Here, we investigated the reciprocal interplay between neuronal endosomes, organelles of central importance for the function of synapses, and synaptic activity. We show that elevated neuronal activity represses the synthesis of endosomal lipid phosphatidylinositol 3-phosphate [PI(3)P] by the lipid kinase VPS34. Neuronal activity in turn is regulated by endosomal PI(3)P, the depletion of which reduces neurotransmission as a consequence of perturbed SV endocytosis. We find that this mechanism involves Calpain 2-mediated hyperactivation of Cdk5 downstream of receptor- and activity-dependent calcium influx. Our results unravel an unexpected function for PI(3)P-containing neuronal endosomes in the control of presynaptic vesicle cycling and neurotransmission, which may explain the involvement of the PI(3)P-producing VPS34 kinase in neurological disease and neurodegeneration.

中文翻译:

内体磷脂酰肌醇 3-磷酸控制突触小泡循环和神经传递。

神经回路功能需要控制神经递质释放和神经元网络活动的机制,包括通过突触接触、突触可塑性和稳态缩放进行调节。然而,神经元如何从本质上监测和反馈控制突触前神经递质释放和突触小泡 (SV) 回收以限制神经元网络活动在分子水平上仍然知之甚少。在这里,我们研究了神经元内体、对突触功能至关重要的细胞器和突触活动之间的相互作用。我们显示升高的神经元活动抑制脂质激酶 VPS34 合成内质脂质磷脂酰肌醇 3-磷酸 [PI(3)P]。反过来,神经元活动受内体 PI(3)P 的调节,由于受干扰的 SV 内吞作用,其消耗减少了神经传递。我们发现这种机制涉及钙蛋白酶 2 介导的 Cdk5 在受体和活性依赖性钙流入下游的过度激活。我们的研究结果揭示了含有 PI(3)P 的神经元内体在控制突触前囊泡循环和神经传递中的意外功能,这可能解释了产生 PI(3)P 的 VPS34 激酶参与神经系统疾病和神经退行性变。
更新日期:2022-03-22
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