Regalado Maria Paz, Terry-Lorenzo Ryan T, Waites Clarissa L, Garner Craig C, Malenka Robert C
Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485, USA.
J Neurosci. 2006 Feb 22;26(8):2343-57. doi: 10.1523/JNEUROSCI.5247-05.2006.
The molecular mechanisms by which postsynaptic modifications lead to precisely coordinated changes in presynaptic structure and function are primarily unknown. To address this issue, we examined the presynaptic consequences of postsynaptic expression of members of the membrane-associated guanylate kinase family of synaptic scaffolding proteins. Postsynaptic expression of synapse-associated protein 97 (SAP97) increased presynaptic protein content and active zone size to a greater extent than comparable amounts of postsynaptic PSD-95 (postsynaptic density-95) or SAP102. In addition, postsynaptic expression of SAP97 enhanced presynaptic function, as measured by increased FM4-64 dye uptake. The structural presynaptic effects of postsynaptic SAP97 required ligand binding through two of its PDZ (PSD-95/Discs large/zona occludens-1) domains as well as intact N-terminal and guanylate kinase domains. Expression of SAP97 recruited a complex of additional postsynaptic proteins to synapses including glutamate receptor 1, Shank1a, SPAR (spine-associated RapGAP), and proSAP2. Furthermore, inhibition of several different transsynaptic signaling proteins including cadherins, integrins, and EphB receptor/ephrinB significantly reduced the presynaptic growth caused by postsynaptic SAP97. These results suggest that SAP97 may play a central role in the coordinated growth of synapses during development and plasticity by recruiting a complex of postsynaptic proteins that enhances presynaptic terminal growth and function via multiple transsynaptic molecular interactions.
突触后修饰导致突触前结构和功能精确协调变化的分子机制目前主要尚不清楚。为了解决这个问题，我们研究了突触支架蛋白膜相关鸟苷酸激酶家族成员在突触后表达的突触前后果。与等量的突触后密度蛋白95（PSD - 95）或突触相关蛋白102（SAP102）相比，突触相关蛋白97（SAP97）在突触后表达时，能更大程度地增加突触前蛋白含量和活性区大小。此外，通过增加FM4 - 64染料摄取量来衡量，突触后SAP97的表达增强了突触前功能。突触后SAP97的突触前结构效应需要通过其两个PDZ（PSD - 95/盘状大蛋白/紧密连接蛋白1）结构域以及完整的N端和鸟苷酸激酶结构域进行配体结合。SAP97的表达使包括谷氨酸受体1、Shank1a、SPAR（棘突相关RapGAP）和proSAP2在内的其他突触后蛋白复合物募集到突触。此外，抑制几种不同的跨突触信号蛋白，包括钙黏蛋白、整合素和EphB受体/ephrinB，可显著降低突触后SAP97引起的突触前生长。这些结果表明，SAP97可能在发育和可塑性过程中突触的协调生长中发挥核心作用，通过募集突触后蛋白复合物，经由多种跨突触分子相互作用增强突触前终末的生长和功能。
