Heteromerization of Ligand Binding Domains of <i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor Requires Both Coagonists, <scp>l</scp>-Glutamate and Glycine

Cheriyan, John; Mezes, Christina; Zhou, Ning; Balsara, Rashna D.

doi:10.1021/bi501437s

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…In contrast, our full-length agonist-bound NMDA receptor structure reveals that the D1-D1 interface remains intact. Indeed, a recent study of isolated LBDs shows that agonist binding stabilizes the GluN1-GluN2 LBD heterodimer (Cheriyan et al, 2015). In light of the ensemble of antagonist-bound NMDAR structures, we propose that binding of glutamate and glycine stabilizes the LBD heterodimer interfaces and gating ring, setting the structural stage for receptor activation (Movie S1).…”

Section: Resultsmentioning

confidence: 99%

Mechanism of NMDA Receptor Inhibition and Activation

Zhu

Stein

Yoshioka

et al. 2016

Cell

193

214

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Summary N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states, and how small molecules inhibit or activate ion channel gating. Here we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating ‘ring’, how agonists retain the ‘ring’ in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ‘ring’ is fundamental to signal transduction and gating in NMDARs.

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Section: Resultsmentioning

confidence: 99%

Mechanism of NMDA Receptor Inhibition and Activation

Zhu

Stein

Yoshioka

et al. 2016

Cell

193

214

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“…L-Glutamate binds to GluN2 subunits, whereas coagonists D-serine and glycine bind to GluN1 subunits (29,35,46). Coagonism is necessary for the heteromeric pairing of ligandbinding domains of NMDA receptor, which is an essential step for forming functional ion channels (12).…”

mentioning

confidence: 99%

N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food

Sasaki

Kinoshita

Matsui

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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d-Serine is abundant in the forebrain and physiologically important for modulating excitatory glutamatergic neurotransmission as a coagonist of synaptic N-methyl-d-aspartate (NMDA) receptor. NMDA signaling has been implicated in the control of food intake. However, the role of d-serine on appetite regulation is unknown. To clarify the effects of d-serine on appetite, we investigated the effect of oral d-serine ingestion on food intake in three different feeding paradigms (one-food access, two-food choice, and refeeding after 24-h fasting) using three different strains of male mice (C57Bl/6J, BKS, and ICR). The effect of d-serine was also tested in leptin signaling-deficient db/db mice and sensory-deafferented (capsaicin-treated) mice. The expression of orexigenic neuropeptides [neuropeptide Y (Npy) and agouti-related protein (Agrp)] in the hypothalamus was compared in fast/refed experiments. Conditioned taste aversion for high-fat diet (HFD) was tested in the d-serine-treated mice. Under the one-food-access paradigm, some of the d-serine-treated mice showed starvation, but not when fed normal chow. HFD feeding with d-serine ingestion did not cause aversion. Under the two-food-choice paradigm, d-serine suppressed the intake of high-preference food but not normal chow. d-Serine also effectively suppressed HFD intake but not normal chow in db/db mice and sensory-deafferented mice. In addition, d-serine suppressed normal chow intake after 24-h fasting despite higher orexigenic gene expression in the hypothalamus. d-Serine failed to suppress HFD intake in the presence of L-701,324, the selective and full antagonist at the glycine-binding site of the NMDA receptor. Therefore, d-serine suppresses the intake of high-preference food through coagonism toward NMDA receptors.

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“…It is a heteromeric cation channel made of two GluN1 subunits and two GluN2 subunits [ 37 ]. For the efficient opening of the ion channel to remove a magnesium block, the NMDA receptor requires membrane depolarization and binding of co-agonists in addition to the binding of the ligand l -glutamate [ 38 ]. Co-agonists bind to the GluN1 subunit, whereas the ligand binds to the GluN2 subunits [ 39 , 40 , 41 ].…”

Section: Nmda Receptor and Its Co-agonists Glycine And Dmentioning

confidence: 99%

Control of Appetite and Food Preference by NMDA Receptor and Its Co-Agonist d-Serine

Sasaki

Matsui

Kitamura

2016

IJMS

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Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body’s homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is necessary to prevent and treat obesity. N-methyl-d-aspartate (NMDA) receptor is a post-synaptic glutamate receptor and is important for excitatory neurotransmission. It is expressed throughout the nervous system, and is important for long-term potentiation. It requires both ligand (glutamate) and co-agonist (d-serine or glycine) for efficient opening of the channel to allow calcium influx. d-serine is contained in fermented foods and marine invertebrates, and brain d-serine level is maintained by synthesis in vivo and supply from food and gut microbiota. Although the NMDA receptor has been reported to take part in the central regulation of appetite, the role of d-serine had not been addressed. We recently reported that exogenous d-serine administration can suppress appetite and alter food preference. In this review, we will discuss how NMDA receptor and its co-agonist d-seine participate in the control of appetite and food preference, and elaborate on how this system could possibly be manipulated to suppress obesity.

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Heteromerization of Ligand Binding Domains of N-Methyl-d-Aspartate Receptor Requires Both Coagonists, l-Glutamate and Glycine

Cited by 6 publications

References 33 publications

Mechanism of NMDA Receptor Inhibition and Activation

Mechanism of NMDA Receptor Inhibition and Activation

N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food

Control of Appetite and Food Preference by NMDA Receptor and Its Co-Agonist d-Serine

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