Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3
Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3
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DOI：
10.1073/pnas.0600304103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Sasaki, Takuya
中科院分区：
文献类型：
--
作者：
Sakane, Ayuko;Manabe, Shinji;Sasaki, Takuya
Rab3A小G蛋白是Rab家族的成员，在脑中最丰富，位于突触囊泡上。越来越多的证据表明Rab3A在神经递质释放和突触可塑性中起关键作用。Rab3A在GDP结合的非活性形式和GTP结合的活性形式之间循环，并且这种活性变化与神经末梢处的突触囊泡的运输周期相关。Rab3 GTP酶激活蛋白（GAP）刺激Rab3A的GTP酶活性，并预期决定Rab3A从突触囊泡解离的时间，这可能与突触囊泡胞吐作用相结合。Rab3 GAP由两个亚基组成：催化亚基p130和非催化亚基p150。最近，发现p130基因突变可引起伴有严重智力低下的瓦尔堡微综合征。在这里，我们产生了p130缺陷小鼠，发现Rab3A的GTP结合形式在大脑中积累。在小鼠中p130的丢失导致抑制Ca2+依赖性谷氨酸释放的突触体和海马CA1区的短期可塑性改变。因此，Rab3 GAP通过限制Rab3A的GTP结合形式的量来调节突触传递和可塑性。
Rab3A small G protein is a member of the Rab family and is most abundant in the brain, where it is localized on synaptic vesicles. Evidence is accumulating that Rab3A plays a key role in neurotransmitter release and synaptic plasticity. Rab3A cycles between the GDP-bound inactive and GTP-bound active forms, and this change in activity is associated with the trafficking cycle of synaptic vesicles at nerve terminals. Rab3 GTPase-activating protein (GAP) stimulates the GTPase activity of Rab3A and is expected to determine the timing of the dissociation of Rab3A from synaptic vesicles, which may be coupled with synaptic vesicle exocytosis. Rab3 GAP consists of two subunits: the catalytic subunit p130 and the noncatalytic subunit p150. Recently, mutations in p130 were found to cause Warburg Micro syndrome with severe mental retardation. Here, we generated p130-deficient mice and found that the GTP-bound form of Rab3A accumulated in the brain. Loss of p130 in mice resulted in inhibition of Ca2+-dependent glutamate release from cerebrocortical synaptosomes and altered short-term plasticity in the hippocampal CA1 region. Thus, Rab3 GAP regulates synaptic transmission and plasticity by limiting the amount of the GTP-bound form of Rab3A.