Architecture and function of NMDA receptors: an evolutionary perspective

• Published in: The Journal of physiology Vol. 599; no. 10; pp. 2615 - 2638
• Main Authors: Stroebel, David, Paoletti, Pierre
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.05.2021; Wiley
• Subjects: Allosteric properties; Biochemistry, Molecular Biology; Biodiversity; Central nervous system; Channel gating; evolution; Evolutionary genetics; glutamate receptors; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Intracellular signalling; Ion channels; Life Sciences; Ligands; ligand‐gated ion channels; Molecular biology; N-Methyl-D-aspartic acid receptors; Nervous system; Neurobiology; Neurons and Cognition; Neurotransmission; NMDA; Phylogeny; Populations and Evolution; Receptor mechanisms; Structural Biology; synapse; Synaptic plasticity; NMDA; neurotransmission; evolution; synapse; ligand-gated ion channels; glutamate receptors; glutamate! receptors; phylogeny
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/JP279028

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. figure legend Molecular specificities of ionotropic glutamate receptors (iGluRs). The center panel illustrates the phylogenetic tree of metazoan iGluRs with its branches colored according to their agonist specificity. The left and right panels depict the molecular and functional signaling at vertebrate synapses of GluAKD (grouping AMPA, kainate and delta receptors) and GluN (grouping NMDARs) receptors, respectively.