Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7136-7141. doi: 10.1073/pnas.1707472114. Epub 2017 Jun 19.
The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD. Remarkably, long-term potentiation (LTP) can override the masking effect of the GFP tag. GluA1, but not GluA2, lacking the ATD fails to show LTP. These findings uncover a role for the ATD in subunit-specific synaptic trafficking of AMPARs, both constitutively and during plasticity. How LTP, induced postsynaptically, engages these extracellular trafficking motifs and what specific cleft proteins participate in the process remain to be elucidated.
AMPA 受体（AMPAR）的氨基末端结构域（ATD）约占蛋白质的 50%，但其功能作用（如果有的话）仍然是个谜。我们发现，表面 GluA1 而不是 GluA2 AMPAR 亚基向突触的易位需要 ATD。缺少 GluA1 的 ATD 的 GluA1A2 异源二聚体不能易位，这确立了 GluA1 的 ATD 的关键作用。将 GFP 插入 ATD 会干扰 GluA1 的组成型突触运输，但不会干扰 GluA2，模拟 ATD 的缺失。值得注意的是，长时程增强（LTP）可以覆盖 GFP 标签的掩蔽效应。缺乏 ATD 的 GluA1 但不是 GluA2 无法显示 LTP。这些发现揭示了 ATD 在 AMPAR 的亚基特异性突触运输中的作用，无论是在组成型还是在可塑性期间。LTP 如何在后突触诱导这些细胞外运输基序，以及哪些特定的裂孔蛋白参与该过程，仍有待阐明。
