Loo Li Shen, Tang Ning, Al-Haddawi Muthafar, Dawe Gavin Stewart, Hong Wanjin
1] Institute of Molecular and Cell Biology, Singapore 138673, Singapore [2] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.
Department of Pharmacology, Neurobiology and Ageing Programme, Singapore Institute for Neurotechnology, National University of Singapore, Singapore 117597, Singapore.
Nat Commun. 2014;5:3176. doi: 10.1038/ncomms4176.
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.
分选连接蛋白27（SNX27）是一种含PDZ结构域的内体蛋白，最近研究表明其在唐氏综合征中可调节谷氨酸受体的再循环。然而，SNX27在GluA1转运中的确切分子作用尚不清楚。在此我们报告，SNX27与再循环内体一起在树突和棘中富集。值得注意的是，观察到SNX27与再循环内体一起向棘中移动。从机制上讲，SNX27通过RA结构域与K-ras GTP酶相互作用；在化学性长时程增强（LTP）刺激后，K-ras通过Ca(2+)/钙调蛋白依赖性机制被募集到富含SNX27的内体，这反过来又驱动同聚体GluA1受体的突触传递。SNX27功能受损会阻止LTP以及AMPA受体相关的转运。这些结果证明了SNX27在神经元可塑性中的作用，为LTP期间的K-ras信号提供了分子解释，并确定SNX27为将可塑性刺激与突触后货物传递相耦合的含PDZ结构域的分子连接物。
