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Pharmacol Res Perspect
2021 Oct 01;95:e00859. doi: 10.1002/prp2.859.
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A glutamate concentration-biased allosteric modulator potentiates NMDA-induced ion influx in neurons.
Costa BM
,
Kwapisz LC
,
Mehrkens B
,
Bledsoe DN
,
Vacca BN
,
Johnston TV
,
Razzaq R
,
Manickam D
,
Klein BG
.
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Precisely controlled synaptic glutamate concentration is essential for the normal function of the N-methyl D-aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration-dependent NMDA receptor modulators would be clinically useful agents with fewer on-target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage-dependent effect. Patch-clamp electrophysiology recordings confirmed agonist concentration-dependent changes in maximum inducible currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration-biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug-like compounds for the treatment of treatment-resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.
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
Al-Hallaq,
NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus.
2007,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets.
2019,
Pubmed
Aluclu,
Evaluation of effects of memantine on cerebral ischemia in rats.
2008,
Pubmed
Balu,
The NMDA Receptor and Schizophrenia: From Pathophysiology to Treatment.
2016,
Pubmed
Balu,
An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia.
2016,
Pubmed
Benneyworth,
Altered acquisition and extinction of amphetamine-paired context conditioning in genetic mouse models of altered NMDA receptor function.
2012,
Pubmed
Bledsoe,
Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity.
2017,
Pubmed
Bledsoe,
Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors.
2019,
Pubmed
Buller,
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition.
1994,
Pubmed
,
Xenbase
CURTIS,
Chemical excitation of spinal neurones.
1959,
Pubmed
CURTIS,
Acidic amino acids with strong excitatory actions on mammalian neurones.
1963,
Pubmed
Chang,
NMDA pathology and treatment of schizophrenia.
2014,
Pubmed
Chatterton,
Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.
2002,
Pubmed
,
Xenbase
Chefer,
Overview of brain microdialysis.
2009,
Pubmed
Cherubini,
Persistent pulsatile release of glutamate induced by N-methyl-D-aspartate in neonatal rat hippocampal neurones.
1991,
Pubmed
Clements,
Transmitter timecourse in the synaptic cleft: its role in central synaptic function.
1996,
Pubmed
Clements,
The time course of glutamate in the synaptic cleft.
1992,
Pubmed
Costa,
Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.
2012,
Pubmed
,
Xenbase
Costa,
A novel family of negative and positive allosteric modulators of NMDA receptors.
2010,
Pubmed
,
Xenbase
Cousins,
Differential interaction of NMDA receptor subtypes with the post-synaptic density-95 family of membrane associated guanylate kinase proteins.
2008,
Pubmed
Coyle,
NMDA receptor and schizophrenia: a brief history.
2012,
Pubmed
Diamond,
Transporters buffer synaptically released glutamate on a submillisecond time scale.
1997,
Pubmed
Dzubay,
The concentration of synaptically released glutamate outside of the climbing fiber-Purkinje cell synaptic cleft.
1999,
Pubmed
Erreger,
Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors.
2007,
Pubmed
,
Xenbase
Evans,
The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons.
2012,
Pubmed
Garthwaite,
Cellular uptake disguises action of L-glutamate on N-methyl-D-aspartate receptors. With an appendix: diffusion of transported amino acids into brain slices.
1985,
Pubmed
Gibb,
A structurally derived model of subunit-dependent NMDA receptor function.
2018,
Pubmed
Hackos,
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
2016,
Pubmed
Hansen,
Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.
2014,
Pubmed
,
Xenbase
Harding,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY.
2018,
Pubmed
Hardingham,
Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated.
2002,
Pubmed
Hardingham,
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.
2010,
Pubmed
Herman,
Extracellular glutamate concentration in hippocampal slice.
2007,
Pubmed
Irvine,
Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors.
2012,
Pubmed
Kane,
Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study.
2015,
Pubmed
Kopec,
Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation.
2006,
Pubmed
Kosinski,
Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: striatum and globus pallidus.
1998,
Pubmed
Kugaya,
Beyond monoamines: glutamatergic function in mood disorders.
2005,
Pubmed
Kuner,
Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels.
1996,
Pubmed
,
Xenbase
Lieberman,
Provocative tests with psychostimulant drugs in schizophrenia.
1987,
Pubmed
Luo,
The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B).
1997,
Pubmed
Madry,
Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function.
2007,
Pubmed
,
Xenbase
Matsuda,
Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors.
2003,
Pubmed
Monaghan,
The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system.
1989,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Moussawi,
Extracellular glutamate: functional compartments operate in different concentration ranges.
2011,
Pubmed
Nahum-Levy,
Desensitization of NMDA receptor channels is modulated by glutamate agonists.
2001,
Pubmed
Okamoto,
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.
2009,
Pubmed
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Parpura,
Homeostatic function of astrocytes: Ca(2+) and Na(+) signalling.
2012,
Pubmed
Peng,
Platelet-derived growth factor protects neurons against gp120-mediated toxicity.
2008,
Pubmed
Perszyk,
Biased modulators of NMDA receptors control channel opening and ion selectivity.
2020,
Pubmed
,
Xenbase
Perszyk,
An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups.
2018,
Pubmed
,
Xenbase
Popescu,
Modes of glutamate receptor gating.
2012,
Pubmed
Rauner,
Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses.
2011,
Pubmed
Rosenmund,
The tetrameric structure of a glutamate receptor channel.
1998,
Pubmed
Schüler,
Formation of NR1/NR2 and NR1/NR3 heterodimers constitutes the initial step in N-methyl-D-aspartate receptor assembly.
2008,
Pubmed
,
Xenbase
Sheng,
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.
1994,
Pubmed
Smothers,
Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits.
2007,
Pubmed
Sontheimer,
Astrocyte Na+ channels are required for maintenance of Na+/K(+)-ATPase activity.
1994,
Pubmed
Stroebel,
Controlling NMDA receptor subunit composition using ectopic retention signals.
2014,
Pubmed
,
Xenbase
Swanger,
Synaptic Receptor Diversity Revealed Across Space and Time.
2018,
Pubmed
Tovar,
Triheteromeric NMDA receptors at hippocampal synapses.
2013,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Volk,
Glutamate synapses in human cognitive disorders.
2015,
Pubmed
Watkins,
Pharmacology of receptors for excitatory amino acids.
1981,
Pubmed
Wells,
The GluN2B-Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand-unbinding and domain opening.
2018,
Pubmed
Zhu,
Structure and symmetry inform gating principles of ionotropic glutamate receptors.
2017,
Pubmed
Zhu,
Mechanism of NMDA Receptor Inhibition and Activation.
2016,
Pubmed
,
Xenbase
von Engelhardt,
GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice.
2015,
Pubmed
Öngür,
Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania.
2008,
Pubmed