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Neuropharmacology
2020 Oct 15;177:108247. doi: 10.1016/j.neuropharm.2020.108247.
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Positive allosteric modulators that target NMDA receptors rectify loss-of-function GRIN variants associated with neurological and neuropsychiatric disorders.
Tang W
,
Liu D
,
Traynelis SF
,
Yuan H
.
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N-methyl-d-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, decreased surface expression, and/or reduced open probability. We have evaluated whether three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and three co-agonists (d-serine, l-serine, and d-cycloserine) can mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 21 different loss-of-function variants in GRIN1, GRIN2A, or GRIN2B, identified in patients with epilepsy, intellectual disability, autism, and/or movement disorders. For all variants, some aspect of the reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.
Adams,
Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.
2014, Pubmed
Adams,
Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.
2014,
Pubmed
Addis,
Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.
2017,
Pubmed
Akazawa,
Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.
1994,
Pubmed
Allen,
De novo mutations in epileptic encephalopathies.
2013,
Pubmed
Amin,
A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability.
2018,
Pubmed
Balu,
The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex.
2012,
Pubmed
Bell,
Disruption of GRIN2B Impairs Differentiation in Human Neurons.
2018,
Pubmed
Billard,
D-Amino acids in brain neurotransmission and synaptic plasticity.
2012,
Pubmed
Burnashev,
NMDA receptor subunit mutations in neurodevelopmental disorders.
2015,
Pubmed
Camp,
GRIN2D/GluN2D NMDA receptor: Unique features and its contribution to pediatric developmental and epileptic encephalopathy.
2020,
Pubmed
Ceccon,
Distinct effect of pregnenolone sulfate on NMDA receptor subtypes.
2001,
Pubmed
Chen,
GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.
2017,
Pubmed
Chen,
Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy.
2017,
Pubmed
Fainberg,
Response to immunotherapy in a patient with Landau-Kleffner syndrome and GRIN2A mutation.
2016,
Pubmed
Farwell,
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.
2015,
Pubmed
Fedele,
Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.
2018,
Pubmed
Fernández-Marmiesse,
A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder.
2018,
Pubmed
,
Xenbase
Gao,
A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.
2017,
Pubmed
Hamdan,
Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
2011,
Pubmed
Hansen,
Structure, function, and allosteric modulation of NMDA receptors.
2018,
Pubmed
Helbig,
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.
2016,
Pubmed
Horak,
Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors.
2004,
Pubmed
Hu,
Human GRIN2B variants in neurodevelopmental disorders.
2016,
Pubmed
Karakas,
Crystal structure of a heterotetrameric NMDA receptor ion channel.
2014,
Pubmed
Lemke,
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
2016,
Pubmed
,
Xenbase
Lemke,
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
2013,
Pubmed
,
Xenbase
Lesca,
GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.
2013,
Pubmed
Li,
De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.
2019,
Pubmed
,
Xenbase
Linsenbardt,
Different oxysterols have opposing actions at N-methyl-D-aspartate receptors.
2014,
Pubmed
,
Xenbase
Lund,
cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.
1999,
Pubmed
MacKay,
D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?
2019,
Pubmed
Malayev,
Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
2002,
Pubmed
,
Xenbase
Masuko,
Stimulatory and inhibitory properties of aminoglycoside antibiotics at N-methyl-D-aspartate receptors.
1999,
Pubmed
,
Xenbase
Myers,
Distinct roles of GRIN2A and GRIN2B variants in neurological conditions.
2019,
Pubmed
O'Roak,
Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.
2012,
Pubmed
Ogden,
Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.
2017,
Pubmed
,
Xenbase
Ohba,
GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.
2015,
Pubmed
Platzer,
GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
2017,
Pubmed
Shin,
Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice.
2020,
Pubmed
Soto,
L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy.
2019,
Pubmed
Stessman,
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.
2017,
Pubmed
Swanger,
Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.
2016,
Pubmed
Traynelis,
Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation.
2017,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Wells,
The GluN2B-Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand-unbinding and domain opening.
2018,
Pubmed
Wilding,
Chimeric Glutamate Receptor Subunits Reveal the Transmembrane Domain Is Sufficient for NMDA Receptor Pore Properties but Some Positive Allosteric Modulators Require Additional Domains.
2016,
Pubmed
Wolosker,
The Neurobiology of d-Serine Signaling.
2018,
Pubmed
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed
XiangWei,
De Novo Mutations and Rare Variants Occurring in NMDA Receptors.
2018,
Pubmed
XiangWei,
Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.
2019,
Pubmed
Yuan,
Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy.
2014,
Pubmed
Yuan,
Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.
2015,
Pubmed
von Stülpnagel,
Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.
2017,
Pubmed
