Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data DOI Creative Commons
Robin Herbrechter,

Nadine Hube,

Raoul Buchholz

et al.

Cellular and Molecular Life Sciences, Journal Year: 2021, Volume and Issue: 78(14), P. 5605 - 5630

Published: June 8, 2021

Abstract Ionotropic glutamate receptors (iGluRs) play key roles for signaling in the central nervous system. Alternative splicing and RNA editing are well-known mechanisms to increase iGluR diversity provide context-dependent regulation. Earlier work on isoform identification has focused analysis of cloned transcripts, mostly from rodents. We here set out obtain a systematic overview human brain based RNA-Seq data. Using data two large-scale transcriptome studies, we established workflow de novo quantification alternative splice events. detected all canonical junctions, assessed abundance events described literature, identified new AMPA, kainate, delta, NMDA receptor subunits. Notable include an abundant transcript encoding GluA4 amino-terminal domain, GluA4-ATD, novel C-terminal GluD1 (delta 1) isoform, GluD1-b, potentially GluK4 GluN2C isoforms. GluN1 may be controlled by inclusion cassette exon, which shows preference one acceptor sites last exon. Moreover, untranslated regions (UTRs) species-specific differences splicing. In contrast, exonic appears limited ten previously sites, result silent amino acid changes. Coupling proximal editing/editing editing/splice occurs variable degree. Overall, this provides first inventory iGluRs impetus further transcriptome-based functional investigations.

Language: Английский

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels DOI Open Access
Kasper B. Hansen, Lonnie P. Wollmuth, Derek Bowie

et al.

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

Citations

466
The Role of Glutamate Receptors in Epilepsy DOI Creative Commons
Tsang‐Shan Chen,

Tzu‐Hsin Huang,

Ming‐Chi Lai

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 783 - 783

Published: March 4, 2023

Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing indispensable role neuronal development and memory formation. The dysregulation of glutamate receptors glutamatergic system involved numerous neurological psychiatric disorders, especially epilepsy. There are two main classes receptor, namely ionotropic metabotropic (mGluRs) receptors. former stimulate fast neurotransmission, N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate; while latter G-protein-coupled that mediate activity via intracellular messenger systems. Glutamate, receptors, regulation astrocytes significantly pathogenesis acute seizure chronic Some receptor antagonists have been shown to be effective for treatment epilepsy, research clinical trials ongoing.

Language: Английский

Citations

86
NMDA receptor functions in health and disease: Old actor, new dimensions DOI Creative Commons
Julien P. Dupuis, Olivier Nicole, Laurent Groc

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(15), P. 2312 - 2328

Published: May 25, 2023

Language: Английский

Citations

67
Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry DOI Creative Commons
Jesse E. Hanson, Hongjie Yuan, Riley E. Perszyk

et al.

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 49(1), P. 51 - 66

Published: June 27, 2023

Abstract N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression schizophrenia, neurodevelopmental such Rett Syndrome, neurodegenerative conditions Alzheimer’s disease. New interest in therapeutic targets has spurred by findings that certain inhibitors produce surprisingly rapid robust antidepressant activity novel mechanism, induction changes brain well outlast presence drug body. These driving research into an entirely new paradigm using antagonists host related conditions. At same time positive allosteric being pursued enhancing function diseases feature hypofunction. While there is great promise, developing must also navigate significant risks posed use agents. We review here emerging pharmacology agents target different subtypes, offering avenues capturing targeting this important class.

Language: Английский

Citations

59
Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both? DOI Creative Commons
Jérémy Hall, Nicholas J. Bray

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 91(8), P. 709 - 717

Published: Oct. 29, 2021

Large-scale genomic studies of schizophrenia have identified hundreds genetic loci conferring risk to the disorder. This progress offers an important route toward defining biological basis condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, exome sequencing analyses schizophrenia, together with functional genomics data pre- postnatal brain, in relation synaptic development function. These provide strong support for view that dysfunction within glutamatergic GABAergic (gamma-aminobutyric acidergic) neurons cerebral cortex, hippocampus, other limbic structures is a central component pathophysiology. Implicated genes suggest disturbances connectivity associated susceptibility begin utero but continue throughout development, some alleles disorder through direct effects on function adulthood. model implies novel interventions could include broad preventive approaches aimed at enhancing health during as well more targeted treatments correcting affected adults.

Language: Английский

Citations

64
Studying Synaptic Connectivity and Strength with Optogenetics and Patch-Clamp Electrophysiology DOI Open Access
Louisa E. Linders, Laura. F. Supiot,

Wenjie Du

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11612 - 11612

Published: Oct. 1, 2022

Over the last two decades combination of brain slice patch clamp electrophysiology with optogenetic stimulation has proven to be a powerful approach analyze architecture neural circuits and (experience-dependent) synaptic plasticity in such networks. Using this methods, originally termed channelrhodopsin-assisted circuit mapping (CRACM), multitude measures functioning can taken. The current review discusses their rationale, applications field, associated caveats. Specifically, addresses: (1) How assess presence connections, both terms ionotropic versus metabotropic receptor signaling, mono- polysynaptic connectivity. (2) acquire interpret for strength function, like AMPAR/NMDAR, AMPAR rectification, paired-pulse ratio (PPR), coefficient variance input-specific quantal sizes. We also address how modulation by G protein-coupled receptors studied pharmacological approaches advanced technology. (3) Finally, we elaborate on advances use dual color optogenetics concurrent investigation multiple pathways. Overall, seek provide practical insights into methods used study synapses, combining patch-clamp electrophysiology.

Language: Английский

Citations

46
GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms DOI Creative Commons
Shasta L. Sabo,

Jessica M. Lahr,

Madelyn Offer

et al.

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

Citations

39
Mechanisms of NMDA receptor regulation DOI Creative Commons
Laétitia Mony, Pierre Paoletti

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 83, P. 102815 - 102815

Published: Nov. 20, 2023

Language: Английский

Citations

32
Nelonemdaz Treatment for Patients With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial DOI

Byeong Jo Chun,

Seok Ran Yeom,

Sung Phil Chung

et al.

Critical Care Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Nelonemdaz is a N-methyl d-aspartate receptor subtype 2B-selective N-methyl-D-aspartate antagonist and potent free-radical scavenger that might ameliorate hypoxic-ischemic brain injury after out-of-hospital cardiac arrest (OHCA). We investigated the efficacy of nelonemdaz for patients with OHCA. A double-blind, placebo-controlled, randomized, multicenter phase II trial. This trial enrolled 105 at five sites in South Korea between November 18, 2018, February 23, 2023. OHCA undergoing targeted temperature management. Patients were randomly assigned to high-dose (5250 mg), low-dose (3250 placebo groups 1:1:1 ratio. median age 61 years (82% male) (n = 37), 35), 33) groups. The primary outcome, serum level neuron-specific enolase (NSE) 48-52 hours, was evaluated 93 patients. There no difference NSE (median interquartile range; 23.7, 15.0-69.9) (17.5, 13.6-113.0) groups, or (26.6, 16.2-83.4) (all p > 0.05). Brain MRI fractional anisotropy significantly higher group compared (0.465, 0.449-0.485 vs. 0.441, 0.431-0.464; 0.028), but not (0.462, 0.439-0.480) (p At day 90, common odds ratio (95% CI) indicating numerically favorable shift modified Rankin Scale 1.25 (0.48-3.24) 1.22 (0.47-3.20) respectively, No serious adverse events reported. treatment did reduce levels controls. treated showed suggesting less cerebral white matter damage.

Language: Английский

Citations

1
Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease DOI Creative Commons
Emyr Lloyd–Evans, Helen Waller‐Evans

Essays in Biochemistry, Journal Year: 2020, Volume and Issue: 64(3), P. 591 - 606

Published: Aug. 5, 2020

Abstract Neurosteroids are steroid hormones synthesised de novo in the brain and peripheral nervous tissues. In contrast to adrenal that act on intracellular nuclear receptors, neurosteroids directly modulate plasma membrane ion channels regulate signalling. This review provides an overview of work led discovery neurosteroids, our current understanding their biosynthetic machinery, roles regulating development function tissue. mediate signalling via multiple mechanisms. Here, we describe detail effects GABA (inhibitory) NMDA (excitatory) two pathways opposing function. Furthermore, emerging evidence points altered neurosteroid neurological disease. focuses neurodegenerative diseases associated with metabolism, mainly Niemann-Pick type C, sclerosis Alzheimer Finally, summarise use natural synthetic as therapeutics alongside potential disease biomarkers.

Language: Английский

Citations

55