Differential regulation of tetramerization of the AMPA receptor glutamate-gated ion channel by auxiliary subunits.
Differential regulation of tetramerization of the AMPA receptor glutamate-gated ion channel by auxiliary subunits.
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DOI：
10.1016/j.jbc.2023.105227
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发表时间：
2023-10
影响因子：
4.8
通讯作者：
Wollmuth, Lonnie P.
中科院分区：
文献类型：
--
作者：
Certain, Noele;Gan, Quan;Bennett, Joseph;Hsieh, Helen;Wollmuth, Lonnie P.
α-氨基-3-羟基-5-甲基-4-异唑烯丙酸受体（AMPAR）辅助亚基是AMPAR的特异性非瞬时结合伙伴，可调节AMPAR通道门控特性、药理学、生物发生和转运。最具特征的辅助亚基家族是跨膜AMPAR调节蛋白（TARPs）、角蛋白同源物（CNIHs）和最近发现的GSG1-L。这些辅助亚基可以促进或减少神经元中由GluA1-4亚基组成的AMPARs的表面表达，从而影响其在膜信号传导中的功能作用。在这里，我们发现CNIH-2增强了WT和突变AMPARs的四聚体化，可能是通过增加四聚体复合物的整体稳定性，这种作用主要是通过与受体的跨膜结构域相互作用介导的。我们还发现CNIH-2和CNIH-3在这方面表现出受体亚基特异性作用，CNIH-2可以增强GluA1和GluA2的四聚化，而CNIH-3只能弱增强GluA1的四聚化。这些结果与CNIHs作为ampar内质网货物转运体的作用一致。相反，TARP γ-2、TARP γ-8和GSG1-L对AMPAR四聚化没有影响或可以忽略不计。另一方面，TARP γ-2可以增强受体的四聚体化，但只有在与受体直接融合达到最大化学计量时才能增强。值得注意的是，CNIH-2比TARP γ-2更能增强功能性AMPARs的表面表达，这表明这种差异有助于成熟和膜表达。这些实验确定了CNIHs和其他辅助亚基在AMPAR生物发生调控中的功能区别。
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) auxiliary subunits are specialized, nontransient binding partners of AMPARs that modulate AMPAR channel gating properties and pharmacology, as well as their biogenesis and trafficking. The most well-characterized families of auxiliary subunits are transmembrane AMPAR regulatory proteins (TARPs), cornichon homologs (CNIHs), and the more recently discovered GSG1-L. These auxiliary subunits can promote or reduce surface expression of AMPARs (composed of GluA1-4 subunits) in neurons, thereby impacting their functional role in membrane signaling. Here, we show that CNIH-2 enhances the tetramerization of WT and mutant AMPARs, presumably by increasing the overall stability of the tetrameric complex, an effect that is mainly mediated by interactions with the transmembrane domain of the receptor. We also find CNIH-2 and CNIH-3 show receptor subunit-specific actions in this regard with CNIH-2 enhancing both GluA1 and GluA2 tetramerization, whereas CNIH-3 only weakly enhances GluA1 tetramerization. These results are consistent with the proposed role of CNIHs as endoplasmic reticulum cargo transporters for AMPARs. In contrast, TARP γ-2, TARP γ-8, and GSG1-L have no or negligible effect on AMPAR tetramerization. On the other hand, TARP γ-2 can enhance receptor tetramerization but only when directly fused with the receptor at a maximal stoichiometry. Notably, surface expression of functional AMPARs was enhanced by CNIH-2 to a greater extent than TARP γ-2, suggesting that this distinction aids in maturation and membrane expression. These experiments define a functional distinction between CNIHs and other auxiliary subunits in the regulation of AMPAR biogenesis.
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