Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms
Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms
复制标题
DOI：
10.1523/jneurosci.0522-06.2006
复制
发表时间：
2006-07-19
影响因子：
5.3
通讯作者：
Okabe, Shigeo
中科院分区：
文献类型：
--
作者：
Kuriu, Toshihiko;Inoue, Akihiro;Okabe, Shigeo
突触后致密物（PSD）的组织化和动态重塑被认为是突触后信号转导的关键，但其分子机制尚不清楚。我们在这里显示，四个主要的支架分子，PSD-95，GKAP，柄，和PSD-Zip 45，每个突触的总分子含量显示出明显的不稳定性。光漂白后的荧光恢复也证实了它们不同的周转率。在所检测的PSD分子中，PSD-95最稳定，但其消除并不影响其直接结合伴侣GKAP的动力学。支架分子与肌动蛋白细胞骨架的多种相互作用表明它们在PSD的维持和重塑中的重要性。事实上，F-肌动蛋白的急性药理学破坏迅速消除了GKAP，Shank和PSD-Zip 45的动态部分，而不改变PSD-95的突触定位。GKAP含量在突触后增加药理学增强神经元的活动，而柄和PSD-Zip 45含量显示减少。抑制F-肌动蛋白动力学阻止了所有三个支架的活性依赖性再分配。我们还评估了谷氨酸受体参与PSD动力学的调节。消除NMDA受体或代谢型谷氨酸受体的遗传操作并不主要影响其结合支架的流动性。这些结果共同表明，丝状肌动蛋白在确定PSD分子组成的动态重组的程度的关键作用。
Organization and dynamic remodeling of postsynaptic density (PSD) are thought to be critical in postsynaptic signal transduction, but the underlying molecular mechanisms are not well understood. We show here that four major scaffolding molecules, PSD-95, GKAP, Shank, and PSD-Zip45, show distinct instability in total molecular content per synapse. Fluorescence recovery after photobleaching also confirmed their distinct turnover rates. Among the PSD molecules examined, PSD-95 was most stable, but its elimination did not influence the dynamics of its direct binding partner GKAP. Multiple interactions of scaffolding molecules with the actin cytoskeleton have suggested their importance in both maintenance and remodeling of the PSD. Indeed, acute pharmacological disruption of F-actin rapidly eliminated the dynamic fraction of GKAP, Shank, and PSD-Zip45, without changing synaptic localization of PSD-95. GKAP content in synapses increased after pharmacological enhancement of neuronal activity, whereas Shank and PSD-Zip45 content showed reduction. Inhibition of F-actin dynamics prevented activity-dependent redistribution of all three scaffolds. We also assessed involvement of glutamate receptors in the regulation of PSD dynamics. Genetic manipulations eliminating either NMDA receptors or metabotropic glutamate receptors did not primarily influence mobility of their binding scaffolds. These results collectively indicate a critical role of filamentous actin in determining the extent of dynamic reorganization in PSD molecular composition.