The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.
The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.
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DOI：
10.1038/ncomms7504
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发表时间：
2015-03-18
影响因子：
16.6
通讯作者：
D'Adamo P
中科院分区：
文献类型：
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作者：
Mignogna ML;Giannandrea M;Gurgone A;Fanelli F;Raimondi F;Mapelli L;Bassani S;Fang H;Van Anken E;Alessio M;Passafaro M;Gatti S;Esteban JA;Huganir R;D'Adamo P
RAB 39 B是以隔室特异性方式控制细胞内囊泡运输的小GTP酶RAB家族的成员。RAB 39 B基因的突变导致智力残疾与自闭症谱系障碍和癫痫共病，但RAB 39 B功能丧失对突触活动的影响在很大程度上无法解释。在这里，我们表明，与C-激酶1（PICK 1）相互作用的蛋白质是GTP结合的RAB 39 B的下游效应子，RAB 39 B-PICK 1控制从内质网到高尔基体的运输，因此，GluA 2，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的亚基的表面表达。AMPAR在突触传递中的作用取决于它们结合的亚基（GluA 1、GluA 2和GluA 3）的组合。小鼠海马神经元中的RAB 39 B下调使AMPAR组合物偏向于不含GluA 2的Ca 2+可渗透形式，从而改变突触活性，特别是在海马神经元中。我们认为，由此产生的突触功能的改变是RAB 39 B相关疾病中认知功能障碍的基础。 编码参与囊泡运输的蛋白质的RAB 39 B基因的突变与智力残疾有关，但RAB 39 B功能丧失对突触活动的影响尚不清楚。在这里，作者表明，RAB 39 B与PICK 1相互作用，这种相互作用是至关重要的AMPA受体亚基易位到高尔基体。
RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca2+-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders. Mutations in the RAB39B gene, which encodes a protein involved in vesicular trafficking, are associated with intellectual disability, but the impact of RAB39B loss of function on synaptic activity is not known. Here the authors show that RAB39B interacts with PICK1, and that this interaction is critical for the translocation of AMPA receptor subunits into the Golgi.