Ecole Normale Supérieure, CNRS, INSERM, Institute de Biologie de l'Ecole Normale Supérieure (IBENS), Université PSL, Paris, France.
J Physiol. 2021 May;599(10):2615-2638. doi: 10.1113/JP279028. Epub 2020 Aug 30.
Ionotropic glutamate receptors (iGluRs) are a major class of ligand-gated ion channels that are widespread in the living kingdom. Their critical role in excitatory neurotransmission and brain function of arthropods and vertebrates has made them a compelling subject of interest for neurophysiologists and pharmacologists. This is particularly true for NMDA receptor (NMDARs), a subclass of iGluRs that act as central drivers of synaptic plasticity in the CNS. How and when the unique properties of NMDARs arose during evolution, and how they relate to the evolution of the nervous system, remain open questions. Recent years have witnessed a boom in both genomic and structural data, such that it is now possible to analyse the evolution of iGluR genes on an unprecedented scale and within a solid molecular framework. In this review, combining insights from phylogeny, atomic structure and physiological and mechanistic data, we discuss how evolution of NMDAR motifs and sequences shaped their architecture and functionalities. We trace differences and commonalities between NMDARs and other iGluRs, emphasizing a few distinctive properties of the former regarding ligand binding and gating, permeation, allosteric modulation and intracellular signalling. Finally, we speculate on how specific molecular properties of iGuRs arose to supply new functions to the evolving structure of the nervous system, from early metazoan to present mammals.
离子型谷氨酸受体 (iGluRs) 是一类广泛存在于生命体中的配体门控离子通道，在节肢动物和脊椎动物的兴奋性神经递质传递和大脑功能中起着至关重要的作用，这使得它们成为神经生理学家和药理学家关注的焦点。特别是 NMDA 受体 (NMDAR)，作为中枢神经系统突触可塑性的核心驱动因素，是 iGluR 的一个亚类。NMDAR 在进化过程中是如何以及何时产生其独特特性的，以及它们与神经系统进化的关系，仍然是悬而未决的问题。近年来，基因组和结构数据呈爆炸式增长，使得现在可以在前所未有的规模和坚实的分子框架内分析 iGluR 基因的进化。在这篇综述中，我们结合系统发育、原子结构以及生理和机制数据的见解，讨论了 NMDAR 基序和序列的进化如何塑造它们的结构和功能。我们追溯了 NMDAR 和其他 iGluR 之间的差异和共同点，强调了前者在配体结合和门控、通透、变构调节和细胞内信号转导方面的几个独特特性。最后，我们推测 iGuRs 的特定分子特性是如何产生的，以向从早期后生动物到现代哺乳动物的不断进化的神经系统结构提供新的功能。
