Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P₂ and PI(5)P.
Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P₂ and PI(5)P.
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DOI：
10.1038/emboj.2012.200
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发表时间：
2012-08-15
期刊：
影响因子：
11.4
通讯作者：
Weisman, Lois S.
中科院分区：
文献类型：
--
作者：
Zhang, Yanling;McCartney, Amber J.;Zolov, Sergey N.;Ferguson, Cole J.;Meisler, Miriam H.;Sutton, Michael A.;Weisman, Lois S.
信号传导脂质PI（3，5）P2和PI（5）P的正常稳态水平需要脂质激酶FAB 1/PIKfyve及其调节剂VAC 14和FIG 4。PIKfyve/VAC 14/FIG 4通路中的突变与人类的Charcot-Marie-Tooth综合征和肌萎缩侧索硬化症以及小鼠的严重神经变性相关。因此，该途径的严格调节对于神经功能至关重要。在这里，我们研究VAC 14在神经元中的定位和生理作用。我们报告说，内源性VAC 14本地化成纤维细胞和神经元的内吞细胞器。出乎意料的是，VAC 14在海马神经元中表现出明显的突触定位，表明其在调节突触功能中的作用。事实上，在Vac 14 −/−和Fig 4 −/−神经元中，微型兴奋性突触后电流的幅度都有所增强。在突触后Vac 14 −/−细胞中重新引入VAC 14可以逆转这种效应。Vac 14 −/−神经元中突触强度的这些变化与AMPA型谷氨酸受体亚基GluA 2的表面水平增强有关，这种效应是由于AMPA受体的调节性内吞作用减弱所致。因此，VAC 14、PI（3，5）P2和/或PI（5）P通过调节AMPA受体的内吞循环在控制突触后功能中起作用。
Normal steady-state levels of the signalling lipids PI(3,5)P2 and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/VAC14/FIG4 pathway are associated with Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14−/− and Fig4−/− neurons. Re-introduction of VAC14 in postsynaptic Vac14−/− cells reverses this effect. These changes in synaptic strength in Vac14−/− neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P2 and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors.
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影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
DOI：
10.1111/j.1600-0854.2009.00915.x
发表时间：
2009-07
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
de Lartigue J;Polson H;Feldman M;Shokat K;Tooze SA;Urbé S;Clague MJ
通讯作者：
Clague MJ
影响因子：
4.8
作者：
BEAL, MF
通讯作者：
BEAL, MF
影响因子：
2.9
作者：
Hirano, Tomoko;Sato, Masa H.
通讯作者：
Sato, Masa H.
影响因子：
3.5
作者：
Ferguson, C. J.;Lenk, G. M.;Meisler, Miriam H.
通讯作者：
Meisler, Miriam H.