Glycine-dependent activation of NMDA receptors

Cummings, Kirstie A.; Popescu, Gabriela

doi:10.1085/jgp.201411302

Cited by 68 publications

(63 citation statements)

References 65 publications

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“…All three are involved in the aminoacyl-tRNA biosynthesis pathway, glycine and serine are part of the cyanoamino acid metabolism, and glycine, serine and threonine metabolism pathways, whereas glutamine is part of the nitrogen metabolism pathway. Glycine, together with serine is an excitatory neurotransmitter in the peripheral nervous system acting as required co-agonists together with glutamate in NMDA receptors (Cummings & Popescu, 2015). Glutamine participates in anabolic processes and the lower abundance in the patient group could be indicative of a slowing of the healing, anabolic processes due to prolonged stress (Jepson, Bates, Broadbent, Pell, & Millward, 1988a, 1988b.…”

Section: Discussionmentioning

confidence: 99%

Plasma metabolomic patterns in patients with exhaustion disorder

Hadrévi

Jonsdottir

Jansson

et al. 2018

Stress

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Exhaustion disorder (ED) is a stress-related disorder that often implies a great burden on the individual patient as well as on society. Previous studies have shown that ED is associated with metabolic deviations, such as lowered fasting glucose. Several mechanisms have been discussed as a plausible explanation of the lack of energy described by these patients. Metabolic processes and reduced ability to mobilize energy have been suggested as important factors. This study investigated metabolomics in 20 patients diagnosed with ED and compared them with 21 healthy controls. Plasma metabolic profiles were examined in both fasting and nonfasting (postprandial) conditions. Blood plasma samples were analyzed for metabolite content using gas chromatography mass spectrometry. A total of 62 different metabolites were simultaneously detected in each of the samples. Multivariate models indicated systematic differences between patients with ED and healthy controls in both their fasting and nonfasting plasma metabolite levels. Lysine and octadecenoic acid were more abundant and glutamine, glycine, serine and gluconic acid were less abundant in the patients across both conditions. In the present study, we comprehensively and simultaneously screen for changes in a large number of metabolites. Our results show a difference in systemic metabolites between patients with exhaustion disorder and healthy controls both in the fasting and in the postprandial states. Here, we present new potential biomarkers mirroring exhaustion disorder metabolism. LAY SUMMARYExhaustion disorder (ED) patients suffer from stress-related symptoms including a reduced energy level. This study investigates the body's metabolism in patients with ED, both fasting and after a meal. New potential markers that may help future investigations on ED were identified. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Plasma metabolomic patterns in patients with exhaustion disorder

Hadrévi

Jonsdottir

Jansson

et al. 2018

Stress

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“…This linear model has been expanded to include glutamate-binding steps 44,84,87 , thus providing a more accurate tool to measure microscopic binding kinetics in separation from gating transitions; and with glycine binding steps 88 . Last, equilibrium activity recorded with an allosteric modulator that selectively stabilized desensitized states provided evidence for two separate desensitization steps, which are most likely accessed from separate pre-open states 89 .…”

Section: Modeling the Operation Of Nmda Receptorsmentioning

confidence: 99%

“…One approach is to exclude from analyses portions of the record that stand out as different and focus on the most prevalent mode 76 ; this approach provides kinetic information for dominant kinetic mode. Alternatively, the entire data set is included and analyzed regardless of possible heterogeneity; in this case, the calculated values for kinetic parameters represent weighted averages across the specific modes that happen to be captured in these records 46,76,82,88,94–98 . As long as these limitations are recognized and acknowledged, and if the perturbations investigated do not affect the channel’s modal transition(s), both approaches are valid and useful.…”

Section: Modeling the Operation Of Nmda Receptorsmentioning

confidence: 99%

NMDA receptors: linking physiological output to biophysical operation

2017

Self Cite

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NMDA receptors are preeminent neurotransmitter-gated channels in the central nervous system, which respond to glutamate in a manner that integrates multiple external and internal cues. They belong to the ionotropic glutamate receptor family and fulfill unique and critical roles in neuronal development and function. These roles depend on characteristic response kinetics, which reflect the receptor’s operation. Here, we review biologically salient features of the NMDA receptor signal and their mechanistic origins. Knowledge of distinctive NMDA receptor biophysical properties, their structural determinants, and physiological roles is necessary to understand the physiologic and neurotoxic actions of glutamate, and to design effective therapeutics.

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“…Recently, precise modeling of the glycine binding and dissociation reactions onto the kinetic model of GluN1/GluN2A receptors placed the glutamate and glycine binding reactions on separate kinetic steps within the activation sequence, namely on C 3 and C 2 , respectively (Figure 1a). This expanded kinetic model predicted accurately all known glycine dependent current behaviors, without the need to postulate agonist-dependent changes in microscopic binding, dissociation, or desensitization rate constants [25]. Although the experimental data refer to GluN1/GluN2A receptors, given the overall conservation in activation mechanisms across GluN1/GluN2 subtypes, it is likely that for other receptor subtypes the conformations that most avidly bind glutamate and glycine are kinetically and structurally distinct.…”

Section: Activation Of Nmda Receptor Subtypesmentioning

confidence: 99%

Kinetic models for activation and modulation of NMDA receptor subtypes

Iacobucci

Popescu

2018

Current Opinion in Physiology

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NMDA receptors are a diverse family of excitatory channels with critical roles in central synaptic transmission, development, and plasticity. Controlled expression of seven subunits and their combinatorial assembly into tetrameric receptors produces a range of molecularly distinct receptor subtypes. Despite relatively similar atomic structures, each subtype has input–output functions with unique biophysical and pharmacologic profiles. Here, we briefly summarize recent advances in understanding how gating and allosteric modulation are similar or distinct across NMDA receptor isoforms and identify open questions that will focus research in this area going forward.

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Glycine-dependent activation of NMDA receptors

Abstract: Results from single-molecule and macroscopic electrophysiology and kinetic analysis provide a model for activation of the glutamate-bound NMDA receptor by glycine.

Cited by 68 publications

References 65 publications

Plasma metabolomic patterns in patients with exhaustion disorder

Plasma metabolomic patterns in patients with exhaustion disorder

NMDA receptors: linking physiological output to biophysical operation

Kinetic models for activation and modulation of NMDA receptor subtypes

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