Tripartite signalling by NMDA receptors

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, Ca 2+ entry and the initiation of Ca 2+ -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.

Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity

“…This is an attractive idea, as limited stimulation of β-cell insulin secretion and β-cell D-serine release could potentiate GSIS acutely, a documented phenomenon of positive feedback previously attributed to other autocrine [ 71 ] and intracellular [ 72 ] mechanisms as well. Additionally, β-cell over-stimulation with repetitive or cumulative D-serine release could prime NMDARs for endocytosis, desensitizing channel modifications and/or trigger non-ionic NMDAR-dependent signaling pathways [ 73 ] that act to limit β-cell excitability, serving as a protection against excitotoxicity or diabetogenic exhaustion. Along these lines, prolonged hyperglycemia was noted to significantly increase inhibitory Grin3a transcripts in Min6 β-cells [ 74 ], while a SNP in this gene has been associated with β-cell dysfunction and new onset diabetes following kidney transplantation [ 75 , 76 ].…”

Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

“…Canonical signalling by NMDARs is mediated by its ionotropic function initiated through simultaneous binding of two molecules of each of the co-agonists glycine (or Dserine) and glutamate to the ligand-binding domains in extracellular regions of the receptor which produces conformational changes that open the cationic conductance pathway of the receptor complex [21,22]. However, increasing evidence is accumulating for non-canonical signalling by NMDARs initiated by independent binding of glycine or glutamate, which does not cause opening of the ionic conductance pathway but which nevertheless causes conformational changes that are transmitted across the membrane resulting in molecular rearrangements within the cell [23]. A striking example of nonionotropic signalling by NMDARs was the discovery [24] that glycine binding to its cognate extracellular site, without binding of glutamate to its cognate site, drives intracellular recruitment of the AP2 endocytic adaptor complex.…”

Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment

“…In addition, the study demonstrated that optogenetics modulation of PV neurons in the mPFC can improve the pathological changes in which the concentration of NAA and GABA in the right mPFC was signi cantly increased, mI was signi cantly reduced, and Glu had a tendency to decrease, simultaneously, the expression of NMDAR was decreased, whereas GAD67 was increased in the mPFC of rats with chronic cerebral ischemia. NMDAR was an important ionic Glu receptor that can mediate Ca 2+ in ux into the post-synaptic membrane and induce post-synaptic depolarization, which is the basis of synaptic plasticity (Rajani et al, 2020). Besides, GABA was synthesized by the decarboxylation of GAD, and then transported by the GABA vesicle transporter to synaptic vesicles, which activates the GABA A receptor to mediate Cl − ow to exert its inhibitory effect (Hwang et al, 2018).…”