Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Nat Neurosci. 2013 Sep;16(9):1266-74. doi: 10.1038/nn.3473. Epub 2013 Jul 21.
Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial in normal synaptic function and neurological disease states. Although transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable AMPARs (CI-AMPARs) and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR-subunit and TARP expression in γ-2-lacking stargazer cerebellar granule cells--the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced the synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, both CP-AMPARs and CI-AMPARs were able to localize to synapses and mediate transmission, although their properties were altered. Our results also establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7 and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice.
钙通透性 AMPA 受体（CP-AMPAR）的调节对于正常的突触功能和神经疾病状态至关重要。尽管跨膜 AMPA 受体调节蛋白（TARPs）如星状蛋白（γ-2）调节钙不可渗透的 AMPA 受体（CI-AMPAR）的特性并促进其突触靶向，但 CP-AMPAR 突触转运的 TARP 特异性规则仍不清楚。我们使用 RNA 干扰来操纵 γ-2 缺乏的星状蛋白缺失型小脑颗粒细胞中的 AMPA 亚基和 TARP 表达-这是 TARP 缺乏的经典模型。我们发现 TARP γ-7 选择性增强 CP-AMPAR 的突触表达并抑制 CI-AMPAR，确定了 γ-7 在调节 CP-AMPAR 普遍性中的关键作用。在没有相关 TARPs 的情况下，CP-AMPAR 和 CI-AMPAR 都能够定位到突触并介导传递，尽管它们的特性发生了改变。我们的结果还表明，颗粒细胞中 TARPed 突触受体需要 γ-2 和 γ-7，并且揭示了星状蛋白缺失型小鼠中 AMPA 介导的传递丧失的意外基础。
