Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor.
Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor.
复制标题
缺乏AP-3B网格蛋白适配器的小鼠中含GABA的突触囊泡的功能不良。
DOI：
10.1083/jcb.200405032
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发表时间：
2004-10-25
影响因子：
7.8
通讯作者：
Ohno, Hiroshi
中科院分区：
文献类型：
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作者：
Nakatsu, Fubito;Okada, Motohiro;Mori, Fumiaki;Kumazawa, Noriko;Iwasa, Hiroto;Zhu, Gang;Kasagi, Yasufumi;Kamiya, Haruyuki;Harada, Akihiro;Nishimura, Kazuhiro;Takeuchi, Arata;Miyazaki, Taisuke;Watanabe, Masahiko;Yuasa, Shigeki;Manabe, Toshiya;Wakabayashi, Koichi;Kaneko, Sunao;Saito, Takashi;Ohno, Hiroshi
AP-3是衔接蛋白（AP）复合物家族的成员，其在分泌和内吞途径中调节货物蛋白的囊泡转运。AP-3有两种亚型：普遍表达的AP-3A和神经元特异性AP-3B。虽然AP-3A的生理作用最近已被阐明，但AP-3B的生理作用仍未得到解决。为了解决这个问题，我们产生了缺乏μ3B的小鼠，μ 3B是AP-3B的一个亚基。μ3B−/−小鼠患有自发性癫痫发作。在这些小鼠的突触处观察到形态学异常。生化研究表明，γ-氨基丁酸（GABA）释放受损，至少部分原因是μ3B−/−小鼠中囊泡GABA转运蛋白的减少。这促进了海马长时程增强的诱导和神经元兴奋性的异常传播通过temporoammonic途径。因此，AP-3B在突触囊泡子集的正常形成和功能中起着关键作用。这项工作增加了一个新的方面癫痫的发病机制。
AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking μ3B, a subunit of AP-3B. μ3B−/− mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of γ-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in μ3B−/− mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.