Glutamate (Glu) is the primary excitatory transmitter in the mammalian brain. But, we know little about the evolutionary history of this adaptation, including the selection of l-glutamate as a signaling molecule in the first place. Here, we used comparative metabolomics and genomic data to reconstruct the genealogy of glutamatergic signaling. The origin of Glu-mediated communications might be traced to primordial nitrogen and carbon metabolic pathways. The versatile chemistry of L-Glu placed this molecule at the crossroad of cellular biochemistry as one of the most abundant metabolites. From there, innovations multiplied. Many stress factors or injuries could increase extracellular glutamate concentration, which led to the development of modular molecular systems for its rapid sensing in bacteria and archaea. More than 20 evolutionarily distinct families of ionotropic glutamate receptors (iGluRs) have been identified in eukaryotes. The domain compositions of iGluRs correlate with the origins of multicellularity in eukaryotes. Although L-Glu was recruited as a neuro-muscular transmitter in the early-branching metazoans, it was predominantly a non-neuronal messenger, with a possibility that glutamatergic synapses evolved more than once. Furthermore, the molecular secretory complexity of glutamatergic synapses in invertebrates (e.g., Aplysia) can exceed their vertebrate counterparts. Comparative genomics also revealed 15+ subfamilies of iGluRs across Metazoa. However, most of this ancestral diversity had been lost in the vertebrate lineage, preserving AMPA, Kainate, Delta, and NMDA receptors. The widespread expansion of glutamate synapses in the cortical areas might be associated with the enhanced metabolic demands of the complex brain and compartmentalization of Glu signaling within modular neuronal ensembles.

谷氨酸（Glu）是哺乳动物大脑中主要的兴奋性递质。但是，我们对这种适应的进化历史知之甚少，包括最初选择L-谷氨酸作为信号分子。在这里，我们使用比较代谢组学和基因组数据来重建谷氨酸信号的谱系。谷氨酸介导的通讯的起源可能可以追溯到原始的氮和碳代谢途径。 L-Glu 的多功能化学性质使该分子成为细胞生物化学的十字路口，成为最丰富的代谢物之一。从那时起，创新成倍增加。许多应激因素或损伤可能会增加细胞外谷氨酸浓度，这导致了模块化分子系统的发展，用于快速传感细菌和古细菌。真核生物中已鉴定出 20 多个进化上不同的离子型谷氨酸受体 (iGluR) 家族。 iGluR 的结构域组成与真核生物多细胞性的起源相关。尽管 L-Glu 在早期分支后生动物中被招募为神经肌肉递质，但它主要是非神经元信使，谷氨酸能突触可能进化不止一次。此外，无脊椎动物（例如海兔）谷氨酸突触的分子分泌复杂性可能超过脊椎动物的对应物。比较基因组学还揭示了后生动物中 15 个以上的 iGluR 亚家族。然而，大多数祖先的多样性在脊椎动物谱系中已经消失，保留了 AMPA、红藻氨酸、Delta 和 NMDA 受体。 皮质区域谷氨酸突触的广泛扩张可能与复杂大脑代谢需求的增强以及模块化神经元群内 Glu 信号传导的划分有关。