In mammalian synapses, the function of ionotropic glutamate receptors is critically modulated by auxiliary subunits. Most of these specifically regulate the synaptic localization and electrophysiological properties of AMPA-type glutamate receptors (AMPARs). Here, we comprehensively investigated the animal evolution of the protein families that contain AMPAR auxiliary subunits (ARASs). We observed that, on average, vertebrates have four times more ARASs than other animal species. We also demonstrated that ARASs belong to four unrelated protein families: CACNG-GSG1, cornichon, shisa and Dispanin C. Our study demonstrates that, despite the ancient origin of these four protein families, the majority of ARASs emerged during vertebrate evolution by independent but convergent processes of neo/subfunctionalization that resulted in the multiple ARASs found in present vertebrate genomes. Importantly, although AMPARs appeared and diversified in the ancestor of bilateral animals, the ARAS expansion did not occur until much later, in early vertebrate evolution. We propose that the surge in ARASs and consequent increase in AMPAR functionalities, contributed to the increased complexity of vertebrate brains and cognitive functions.

在哺乳动物突触中，离子型谷氨酸受体的功能受到辅助亚基的严格调节。其中大多数专门调节 AMPA 型谷氨酸受体 (AMPAR) 的突触定位和电生理特性。在这里，我们全面研究了包含 AMPAR 辅助亚基 (ARAS) 的蛋白质家族的动物进化。我们观察到，平均而言，脊椎动物的 ARAS 是其他动物物种的四倍。我们还证明 ARAS 属于四个不相关的蛋白质家族：CACNG-GSG1、cornichon、shisa 和 Dispanin C。我们的研究表明，尽管这四个蛋白质家族的起源很古老，大多数 ARAS 在脊椎动物进化过程中通过新/亚功能化的独立但聚合过程出现，导致在目前的脊椎动物基因组中发现了多个 ARAS。重要的是，虽然 AMPAR 在双侧动物的祖先中出现并多样化，但 ARAS 扩展直到很久以后才发生，在早期脊椎动物进化中。我们提出，ARAS 的激增和随之而来的 AMPAR 功能的增加，导致了脊椎动物大脑和认知功能的复杂性增加。