AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability.
AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability.
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DOI：
10.1038/ncomms15910
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发表时间：
2017-07-04
影响因子：
16.6
通讯作者：
Fakler B
中科院分区：
文献类型：
--
作者：
Brechet A;Buchert R;Schwenk J;Boudkkazi S;Zolles G;Siquier-Pernet K;Schaber I;Bildl W;Saadi A;Bole-Feysot C;Nitschke P;Reis A;Sticht H;Al-Sanna'a N;Rolfs A;Kulik A;Schulte U;Colleaux L;Abou Jamra R;Fakler B
AMPA型谷氨酸受体（AMPA-type glutamate receptor，AMPAR）是脑内兴奋性神经传递的关键元件，是一种大分子复合物，其性质和细胞功能由其蛋白质组的共组装成分决定。在这里，我们确定的AMPAR复合物，瞬时形成的内质网（ER）和缺乏核心亚基典型的AMPAR在质膜。这些ER AMPAR的中心成分是蛋白质组成分FRRS 11（C9 orf 4）和CPT 1c，它们特异性地和协同地结合到AMPAR的成孔GluA 1 -4蛋白上。人类FRRS 1 L基因中的双等位基因突变被证明会导致严重的智力残疾，包括认知障碍、言语延迟和癫痫活动。病毒介导的FRRS 11的缺失或过表达通过减少或增加突触和突触外位点中AMPAR的数量来强烈影响成年大鼠脑中的突触传递。我们的研究结果提供了对AMPAR的早期生物发生的深入了解，并证明了其对突触传递和脑功能的显著影响。AMPA型谷氨酸受体（AMPAR）复合物的生物起源仅部分了解。在这里，作者鉴定了GluA 1 -4蛋白和蛋白FRRS 1 l/CPT 1c的瞬时组装，这些蛋白驱动ER中成熟AMPAR复合物的形成。FRRS 11突变与三个家族中的智力残疾和癫痫相关。
AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function. The biogenesis of AMPA-type glutamate receptor (AMPAR) complexes is only partially understood. Here the authors identify transient assemblies of GluA1-4 proteins and proteins FRRS1l/CPT1c that drive formation of mature AMPAR complexes in the ER. Mutations in FRRS1l are associated with intellectual disability and epilepsy in three families.
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