GSG1L-containing AMPA receptors are complexes with unique spatiotemporal expression, subunit composition and gating properties

Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that profoundly regulate glutamatergic synapse strength and plasticity. While AMPAR-TARP complexes have been extensively studied, less is known about the GSG1L-containing AMPAR complex. Here, we show that GSG1L’s spatiotemporal expression, native interactome and allosteric sites are distinct. GSG1L generally expresses late during brain development in a cell-type and region-specific manner, finally constituting about 5% of all AMPAR complexes in the adult brain (at adulthood). While GSG1L can co-assemble with cornichon and TARP subunits into AMPAR complexes, it may also form the sole auxiliary subunit. Unexpectedly, GSG1L acts through two discrete, evolutionarily-conserved sites on the agonist-binding domain with a weak allosteric interaction at the KGK site, shared with TARPs to slow AMPAR desensitization, and a stronger interaction at a novel site that slows recovery from desensitization.

跨膜AMPA受体调节蛋白（TARPs）与生殖细胞特异性基因1样蛋白（GSG1L）均属于紧密连接蛋白家族型AMPA受体（AMPAR）辅助亚基，可显著调控谷氨酸能突触的强度与可塑性。尽管AMPA受体-TARP复合物已被广泛研究，但针对含GSG1L的AMPA受体复合物的认知仍较为有限。本研究表明，GSG1L的时空表达模式、天然相互作用组以及变构位点均具有独特性。GSG1L在脑发育过程中晚期表达，且呈现细胞类型与区域特异性分布，最终在成年大脑中占所有AMPA受体复合物的约5%。尽管GSG1L可与cornichon及TARP亚基共同组装进入AMPA受体复合物，但其也可作为唯一的辅助亚基存在。出乎意料的是，GSG1L通过AMPA受体的激动剂结合域上两个独立且进化保守的位点发挥作用：其一为与TARPs共有的KGK位点，可通过较弱的变构相互作用延缓AMPA受体的脱敏反应；其二为全新的位点，可通过更强的变构相互作用延缓脱敏后的恢复过程。