Contributions by N-terminal Domains to NMDA Receptor Currents

Amico-Ruvio, Stacy A.; Paganelli, Meaghan A.; Abbott, Jamie A.; Myers, John M.; Kasperek, Eileen M.; Iacobucci, Gary J.; Popescu, Gabriela

doi:10.1101/2020.08.21.261388

Cited by 5 publications

(4 citation statements)

References 67 publications

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“…Amino-terminal domain conformations dictate differences in receptor activation 22, 50 . Decoupling of the amino-terminal domain upon antagonist or inhibitor binding correlates with lower activity of GluN1/GluN2A and GluN1/GluN2B receptors 29, 51 .…”

Section: Resultsmentioning

confidence: 99%

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bender,

Chakraborty,

Durham

et al. 2024

Preprint

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N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilized single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains.

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Section: Resultsmentioning

confidence: 99%

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bender,

Chakraborty,

Durham

et al. 2024

Preprint

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“…Expression of the sodium-calcium exchange gene NCX influenced by cerebral ischemia may ameliorate the consequences of ischemic brain damage, but decreased expression in the NMDAR-mediated NCX gene results in calcium overload. When excitotoxicity occurs, there is also an increase in mitochondrial calcium concentration, which produces ROS and will induce neuronal cell death [16].…”

Section: Literature Reviewmentioning

confidence: 99%

“…In stroke, NR2AR and NR2BR are subunits required for glutamate mediation and are associated with neuronal cell death and neuronal cell survival. Under normal conditions, NMDAR (NR2A dominant) synaptic transmission stimulates neuronal survival (NSC) signaling, but under pathological conditions, an increase in extracellular glutamate concentration causes excitatory and excessive NMDAR (NR2B dominant) synaptic activation [16]. Activation of NR2B causes an increase in calcium, promotes ADAPK (active deathassociated protein kinase), and binds to NR2B [17].…”

Section: Literature Reviewmentioning

confidence: 99%

Characteristics of Ischemic Stroke Patients Performed by DSA Actions at Chasbullah Abdul Madjid Bekasi Regional General Hospital

Utom

Tobing

Natasha

2022

Int J Health Sci Res

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Stroke has become the second leading cause of death and the third leading disability globally caused by several factors, such as hypertension, diabetes Mellitus, atrial fibrillation, and cholesterol. DSA (Digital Subtraction Angiography) has been the gold standard for diagnosing abnormalities in cerebrovascular, such as aneurysms and malformation artery and vena. Cerebral DSA is a safe procedure and has the advantage that intervention procedures such as stent insertion or thrombectomy can be performed immediately after angiography. This research is intended to find the characteristic of a stroke patient treated with Digital Subtraction Angiography. The design used in the study is retrospective with a medical record of a stroke ischemic patient who was treated with Digital Subtraction Angiography at RSUD CAM Bekasi from August 2020 - to June 2021. The sampling technique of this study was taken using total sampling techniques; namely, the entire population that the researcher had determined was a research sample. Forty-nine patients are used as the research sample according to the inclusive criteria. As a result, it has been found that the demographic in which Digital Subtraction Angiography has been utilized is 41-59 years old (61.2%), of which 65.3% of them are male patients. Based on their education, most of them come from strata 1, sitting at 61.2%, and their occupation is commercial workers, sitting at 26.5%. Risk factors that come with Digital Subtraction Angiography are hypertension (91.8%) and vertigo symptoms (55.1%). For motoric patients, 12.3% have seen improvements. Meanwhile, according to the National Institute of Health Stroke Scale, 46.9% have seen improvements. Digital Subtraction Angiography results show that 53.1% of ischemic stroke patients have improved. Key words: Stroke Ischemic, Digital Subtraction Angiography.

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“…About two-thirds of residues are extracellular and are organized into two layers, each consisting of four globular domains. The membrane-distal N-terminal layer forms modulator-binding sites and influences the channel open probability, but is dispensable to agonist-dependent activation 15, 16 . Likely, mutations in this layer affect the receptor’s sensitivity to allosteric modulators.…”

Section: Introductionmentioning

confidence: 99%

Complex functional phenotypes of NMDA receptor disease variants

Iacobucci

Liu

Wen

et al. 2022

Preprint

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NMDA receptors have essential roles in the physiology of central excitatory synapses and their dysfunction causes severe neuropsychiatric symptoms. Recently, a series of genetic variants have been identified in patients, however, functional information about these variants is sparse and their role in pathogenesis insufficiently known. Here we investigate the mechanism by which two GluN2A variants may be pathogenic. We use molecular dynamics simulation and single-molecule electrophysiology to examine the contribution of GluN2A subunit-residues, P552 and F652, and their pathogenic substitutions, P552R and F652V, affect receptor functions. We found that P552 and F652 interact during the normal activity cycle of the receptor; the interaction stabilizes receptors in open conformations and is required for a normal electrical response. Engineering shorter side-chains at these positions (P552A and/or F652V) caused a loss of interaction energy and produced receptors with severe gating, conductance, and permeability deficits. In contrast, the P552R sidechain resulted in stronger interaction and produced a distinct, yet still drastically abnormal electrical response. These results identify the dynamic contact between P552 and F652 as a critical step in the NMDA receptor activation, and show that both increased and reduced communication through this interaction cause dysfunction. Results show that subtle differences in NMDA receptor primary structure can generate complex phenotypic alterations whose binary classification is too simplistic to serve as a therapeutic guide.

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Contributions by N-terminal Domains to NMDA Receptor Currents

Cited by 5 publications

References 67 publications

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Characteristics of Ischemic Stroke Patients Performed by DSA Actions at Chasbullah Abdul Madjid Bekasi Regional General Hospital

Complex functional phenotypes of NMDA receptor disease variants

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