GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites
GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites
复制标题
DOI：
10.1073/pnas.1304301111
复制
发表时间：
2014-04-01
影响因子：
11.1
通讯作者：
Kneussel, Matthias
中科院分区：
文献类型：
--
作者：
Heisler, Frank F.;Lee, Han Kyu;Kneussel, Matthias
AMPA 型谷氨酸受体 (AMPAR) 的 GluA2 亚基调节神经元中的兴奋性突触传递。此外，跨突触细胞粘附分子 N-钙粘蛋白控制兴奋性突触功能并稳定树突棘结构。在突触后膜，GluA2 与 N-钙粘蛋白物理结合，促进脊柱生长和突触调节。我们报道 N-钙粘蛋白通过其细胞内 C 末端与谷氨酸受体相互作用蛋白 1 (GRIP1) 的 PSD-95/SAP90/DLG/ZO-1 (PDZ) 结构域 2 结合。 N-钙粘蛋白和含有 GluA2 的 AMPAR 被预分选到相同的转运囊泡中进行树突递送，实时成像揭示了两种蛋白质的共转运。驱动蛋白 KIF5 通过使用 GRIP1 作为多链路接口为 GluA2/N-钙粘蛋白代码传递提供动力。值得注意的是，GluA2 和 N-钙粘蛋白使用 GRIP1 上不同的 PDZ 结构域来同时结合转运复合物，并且干扰任一结合基序都会损害两种突触货物的周转。微管的解聚、KIF5 运动结构域的缺失或 AMPAR 胞吐作用的特异性阻断会影响 GluA2/N-钙粘蛋白囊泡的递送。在功能水平上，干扰这种协同转运会减少脊柱突起和兴奋性突触的数量。我们的数据表明，多 PDZ 结构域接头蛋白 GRIP1 可以充当运输囊泡的支架，将 AMPAR 和 N-钙粘蛋白联合递送到树突中。
The GluA2 subunit of AMPA-type glutamate receptors (AMPARs) regulates excitatory synaptic transmission in neurons. In addition, the transsynaptic cell adhesion molecule N-cadherin controls excitatory synapse function and stabilizes dendritic spine structures. At postsynaptic membranes, GluA2 physically binds N-cadherin, underlying spine growth and synaptic modulation. We report that N-cadherin binds to PSD-95/SAP90/DLG/ZO-1 (PDZ) domain 2 of the glutamate receptor interacting protein 1 (GRIP1) through its intracellular C terminus. N-cadherin and GluA2-containing AMPARs are presorted to identical transport vesicles for dendrite delivery, and live imaging reveals cotransport of both proteins. The kinesin KIF5 powers GluA2/N-cadherin codelivery by using GRIP1 as a multilink interface. Notably, GluA2 and N-cadherin use different PDZ domains on GRIP1 to simultaneously bind the transport complex, and interference with either binding motif impairs the turnover of both synaptic cargoes. Depolymerization of microtubules, deletion of the KIF5 motor domain, or specific blockade of AMPAR exocytosis affects delivery of GluA2/N-cadherin vesicles. At the functional level, interference with this cotransport reduces the number of spine protrusions and excitatory synapses. Our data suggest the concept that the multi-PDZ-domain adaptor protein GRIP1 can act as a scaffold at trafficking vesicles in the combined delivery of AMPARs and N-cadherin into dendrites.