Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(4), P. 1469 - 1658

Published: Oct. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Language: Английский

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Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

F1000Research, Journal Year: 2019, Volume and Issue: 8, P. 1940 - 1940

Published: Nov. 20, 2019

Rapid advances in sequencing technology have led to an explosive increase the number of genetic variants identified patients with neurological disease and also enabled assembly a robust database healthy individuals. A surprising GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits been found various neuropsychiatric disorders, including autism spectrum epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia. This review compares contrasts available information describing clinical functional consequences variations GRIN2A GRIN2B. Comparison phenotypes shows are commonly associated epileptic phenotype but GRIN2B neurodevelopmental disorders. These observations emphasize distinct roles gene products serve circuit function suggest analysis variation may provide insight into molecular mechanisms, which will allow more accurate subclassification phenotypes. Furthermore, characterization pharmacological properties variant receptors could first opportunity for translational therapeutic strategies these GRIN-related psychiatric

Language: Английский

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Regulation of NMDA glutamate receptor functions by the GluN2 subunits

Journal of Neurochemistry, Journal Year: 2020, Volume and Issue: 154(2), P. 121 - 143

Published: Jan. 24, 2020

Abstract The N ‐methyl‐ D ‐aspartate receptors (NMDARs) are ionotropic glutamate that mediate the flux of calcium (Ca 2+ ) into post‐synaptic compartment. Ca influx subsequently triggers activation various intracellular signalling cascades underpin multiple forms synaptic plasticity. Functional NMDARs assembled as heterotetramers composed two obligatory GluN1 subunits and GluN2 or GluN3 subunits. Four different (GluN2A‐D) present throughout central nervous system; however, they differentially expressed, both developmentally spatially, in a cell‐ synapse‐specific manner. Each subunit confers with distinct ion channel properties trafficking pathways. Regulated membrane is dynamic process ultimately determines number at synapses, controlled by subunit‐specific interactions regulatory proteins. Here we review recent progress made towards understanding molecular mechanisms regulate GluN2‐containing NMDARs, focusing on roles several key proteins interact via their carboxyl termini. image

Language: Английский

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Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Cell, Journal Year: 2020, Volume and Issue: 182(2), P. 357 - 371.e13

Published: June 30, 2020

Language: Английский

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Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 26(5), P. 1505 - 1519

Published: Aug. 6, 2019

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as risk for ASD and other neuropsychiatric disorders. However, whether how Dock4 disruption leads to features through mechanism remain unexplored. We generated characterized line knockout (KO) mice, which intriguingly displayed series ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, perturbed object spatial learning. Mice with conditional deletion in hippocampal CA1 recapitulated preference deficit KO mice. Examination pyramidal neurons excitatory transmission was drastically attenuated accompanied by decreased spine density content AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, deficiency markedly reduced activity hippocampus, resulted downregulation global protein synthesis diminished expression receptor subunits. Notably, replenishment mice restored corrected deficits these pharmacological activation receptors also Together, our findings uncover previously unrecognized Dock4-Rac1-dependent involved regulating behavior.

Language: Английский

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Improved prediction of solvation free energies by machine-learning polarizable continuum solvation model

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 18, 2021

Abstract Theoretical estimation of solvation free energy by continuum models, as a standard approach in computational chemistry, is extensively applied broad range scientific disciplines. Nevertheless, the current widely accepted models are either inaccurate reproducing experimentally determined energies or require number macroscopic observables which not always readily available. In present study, we develop and introduce Machine-Learning Polarizable Continuum Model (ML-PCM) for substantial improvement predictability energy. The performance reliability developed validated through rigorous demanding validation procedure. ML-PCM study improve accuracy almost one order magnitude with no additional costs. A freely available software provided straightforward implementation new approach.

Language: Английский

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Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Jan. 7, 2022

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury inflammation, thereby they may participate epileptogenesis. NMDARs belong to a family ionotropic glutamate essential roles excitatory neurotransmission synaptic plasticity mammalian CNS. Despite numerous focusing on NMDAR epilepsy, relationship appeared be elusive. In this article, we reviewed regulation possible mechanisms respect onset, development, treatment, trying provide more evidence for future studies.

Language: Английский

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GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms

Frontiers in Synaptic Neuroscience, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 10, 2023

The GRIN2B -related neurodevelopmental disorder is a rare disease caused by mutations in the gene, which encodes GluN2B subunit of NMDA receptors. Most individuals with present intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, epilepsy are also common. A large number pathogenic de novo have been identified . However, it not yet known how these variants lead to clinical symptoms disease. Recent research has begun address this issue. Here, we describe key experimental approaches that used better understand pathophysiology We discuss impact several distinct on receptor properties. then critically review pivotal studies examining synaptic phenotypes observed when disease-associated expressed neurons. These data provide compelling evidence various mutants interfere neuronal differentiation, dendrite morphogenesis, synaptogenesis, plasticity. Finally, identify important open questions considerations for future aimed at understanding complex Together, existing insight into pathophysiological mechanisms underlie emphasize importance comparing effects individual, variants. Understanding molecular, cellular circuit produced wide range should identification core characterize its symptoms. This information could help guide development application effective therapeutic strategies treating disorder.

Language: Английский

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Structural insights into the diverse actions of magnesium on NMDA receptors

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

Children, Journal Year: 2025, Volume and Issue: 12(4), P. 481 - 481

Published: April 8, 2025

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, neuromodulation, but often fail to address the underlying pathophysiology or improve outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms emerging as promising disease-modifying approaches. This narrative review explores therapeutic strategies for based pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, targeted pharmacotherapy, antisense oligonucleotides, gene repurposing existing with mechanism-specific effects. Early intervention may not only control could also potentially prevent progression susceptible populations. Future directions developing computable phenotypes accurate diagnosis, refining subgrouping, enhancing drug development, advancing gene-based therapies, personalizing implementing adaptive clinical trial designs, ensuring equitable access While significant challenges remain, integrating biological insights innovative offers new hope transforming treatment from symptomatic disease modification.

Language: Английский

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