Abstract
N-methyl-d-aspartate receptors (NMDARs) are excitatory glutamatergic receptors that are fundamental for many neuronal processes, including synaptic plasticity. NMDARs are comprised of four subunits derived from heterogeneous subunit families, yielding a complex diversity in NMDAR form and function. The quadruply-liganded state of binding of two glutamate and two glycine molecules to the receptor drives channel gating, allowing for monovalent cation flux, Ca2+ entry and the initiation of Ca2+-dependent signalling. In addition to this ionotropic function, non-ionotropic signalling can be initiated through the exclusive binding of glycine or of glutamate to the NMDAR. This binding may trigger a transmembrane conformational change of the receptor, inducing intracellular protein-protein signalling between the cytoplasmic domain and secondary messengers. In this review, we outline signalling cascades that can be activated by NMDARs and propose that the receptor transduces signalling through three parallel streams: (i) signalling via both glycine and glutamate binding, (ii) signalling via glycine binding, and (iii) signalling via glutamate binding. This variety in signal transduction mechanisms and downstream signalling cascades complements the widespread prevalence and rich diversity of NMDAR activity throughout the central nervous system and in disease pathology.
Highlights
NMDA receptors (NMDARs) are excitatory glutamatergic receptors that are found throughout the mammalian central nervous system (CNS) and are fundamental to many neuronal processes
The non-ionotropic functions of NMDARs are mediated through ligand binding to the extracellular agonist-binding domain (ABD) which is hypothesized to induce conformational changes that are transduced across the cell membrane to effect
That ligand binding may initiate transmembrane signalling from the ABD to the C-terminal domain (CTD), triggering changes in intracellular protein-protein interactions is supported by the use of fluorescence lifetime imaging and fluorescence resonance energy transfer which have detected the movement of Glycine-binding NMDA receptor subunit 1 (GluN1) cytoplasmic domains in response to extracellular Glutamate-binding NMDA receptor subunit 2 (GluN2) binding, in the presence of Ion pore blocker (MK-801) and 7-CK [52]
Summary
NMDA receptors (NMDARs) are excitatory glutamatergic receptors that are found throughout the mammalian central nervous system (CNS) and are fundamental to many neuronal processes. The non-ionotropic functions of NMDARs are mediated through ligand binding to the extracellular ABD which is hypothesized to induce conformational changes that are transduced across the cell membrane to effect
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