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Physiological Research 2014NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in... (Review)
Review
NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.
Topics: Animals; Brain; Brain Diseases; Humans; Ion Channel Gating; Neurons; Neuroprotective Agents; Protein Conformation; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Synaptic Transmission
PubMed: 24564659
DOI: 10.33549/physiolres.932678 -
Biomolecules Jun 2020N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both... (Review)
Review
N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.
Topics: Animals; Brain; Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 32585886
DOI: 10.3390/biom10060947 -
The Journal of General Physiology Aug 2018NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca-permeable component of excitatory neurotransmission in the central nervous system (CNS).... (Review)
Review
NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
Topics: Animals; Humans; Ions; Protein Structure, Quaternary; Receptors, N-Methyl-D-Aspartate
PubMed: 30037851
DOI: 10.1085/jgp.201812032 -
Nature Apr 2018The NMDA (N-methyl-D-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel . Owing to the...
The NMDA (N-methyl-D-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.
Topics: Alzheimer Disease; Animals; Binding Sites; Crystallography, X-Ray; Dizocilpine Maleate; Ion Channel Gating; Memantine; Molecular Dynamics Simulation; Protein Domains; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Substrate Specificity; Xenopus
PubMed: 29670280
DOI: 10.1038/s41586-018-0039-9 -
Cold Spring Harbor Perspectives in... Jun 2012Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident...
Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.
Topics: Humans; Learning; Long-Term Potentiation; Long-Term Synaptic Depression; Memory; Receptors, N-Methyl-D-Aspartate; Signal Transduction
PubMed: 22510460
DOI: 10.1101/cshperspect.a005710 -
Neuropharmacology Jan 2022NMDA receptors are one subtype of glutamate receptor that play fundamental roles in synaptic physiology and synaptic plasticity in the nervous system, in addition to... (Review)
Review
NMDA receptors are one subtype of glutamate receptor that play fundamental roles in synaptic physiology and synaptic plasticity in the nervous system, in addition to being implicated in several neurological disorders. It is now established that many NMDA receptors in the nervous system are triheteromeric, composed of two glycine-binding GluN1 subunits and two different glutamate binding GluN2 subunits. The pharmacology of NMDA receptor has become well established since the pioneering work of Watkins and Evans almost half a century ago and has seen a resurgence of interest in the past decade as new subtype-selective allosteric modulators have been discovered. In this article, features specific to allosteric antagonist action at triheteromeric NMDA receptors are reviewed with a focus on understanding the mechanism of action of drugs acting at triheteromeric GluN1/GluN2B/GluN2D receptors. These receptors are of importance in the basal ganglia and in interneurons of the hippocampus and implications for understanding the action of allosteric antagonists at synaptic triheteromeric receptors are considered.
Topics: Allosteric Regulation; Animals; Basal Ganglia; Binding Sites; Glutamic Acid; Glycine; Hippocampus; Humans; Interneurons; Nervous System Diseases; Neuronal Plasticity; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission
PubMed: 34736958
DOI: 10.1016/j.neuropharm.2021.108861 -
Advances in Pharmacology (San Diego,... 2016Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be... (Review)
Review
Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be a neurodevelopmental disorder that results from a combination of environmental insults and genetic vulnerabilities. Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-d-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process. This review describes the structure-function relationship of the NMDAR channel and how the glycine modulatory site acts as an important regulator of its activity. In addition, this review highlights the genetic, pharmacologic, and biochemical evidence supporting the hypothesis that NMDAR hypofunction contributes to the pathophysiology of schizophrenia. Finally, this chapter highlights some of the most recent and promising pharmacological strategies that are designed to either, directly or indirectly, augment NMDAR function in an effort to treat the cognitive and negative symptoms of schizophrenia that are not helped by currently available medications.
Topics: Animals; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction
PubMed: 27288082
DOI: 10.1016/bs.apha.2016.01.006 -
Biochemical Society Transactions Aug 2023N-methyl-d-aspartate receptors (NMDARs) comprise a subfamily of ionotropic glutamate receptors that form heterotetrameric ligand-gated ion channels and play fundamental... (Review)
Review
N-methyl-d-aspartate receptors (NMDARs) comprise a subfamily of ionotropic glutamate receptors that form heterotetrameric ligand-gated ion channels and play fundamental roles in neuronal processes such as synaptic signaling and plasticity. Given their critical roles in brain function and their therapeutic importance, enormous research efforts have been devoted to elucidating the structure and function of these receptors and developing novel therapeutics. Recent studies have resolved the structures of NMDARs in multiple functional states, and have revealed the detailed gating mechanism, which was found to be distinct from that of other ionotropic glutamate receptors. This review provides a brief overview of the recent progress in understanding the structures of NMDARs and the mechanisms underlying their function, focusing on subtype-specific, ligand-induced conformational dynamics.
Topics: Receptors, N-Methyl-D-Aspartate; Receptors, Ionotropic Glutamate; Signal Transduction; Cell Communication
PubMed: 37431773
DOI: 10.1042/BST20230122 -
International Journal of Molecular... Jul 2016Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive... (Review)
Review
Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body's homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is necessary to prevent and treat obesity. N-methyl-d-aspartate (NMDA) receptor is a post-synaptic glutamate receptor and is important for excitatory neurotransmission. It is expressed throughout the nervous system, and is important for long-term potentiation. It requires both ligand (glutamate) and co-agonist (d-serine or glycine) for efficient opening of the channel to allow calcium influx. d-serine is contained in fermented foods and marine invertebrates, and brain d-serine level is maintained by synthesis in vivo and supply from food and gut microbiota. Although the NMDA receptor has been reported to take part in the central regulation of appetite, the role of d-serine had not been addressed. We recently reported that exogenous d-serine administration can suppress appetite and alter food preference. In this review, we will discuss how NMDA receptor and its co-agonist d-seine participate in the control of appetite and food preference, and elaborate on how this system could possibly be manipulated to suppress obesity.
Topics: Appetite; Dopamine; Food Preferences; Glutamic Acid; Humans; Obesity; Receptors, N-Methyl-D-Aspartate; Serine
PubMed: 27399680
DOI: 10.3390/ijms17071081 -
Turkish Neurosurgery 2021To investigate the expression patterns of D-serine and N-methyl-D-aspartate (NMDA) receptor 1 in the temporal lobes of patients with intractable epilepsy.
AIM
To investigate the expression patterns of D-serine and N-methyl-D-aspartate (NMDA) receptor 1 in the temporal lobes of patients with intractable epilepsy.
MATERIAL AND METHODS
Cortical temporal lobe brain tissue samples were collected from 20 patients with intractable epilepsy and 6 patients with brain trauma. The expression patterns of D-serine and NMDA receptor 1 were detected by immunofluorescence staining and western blot analysis.
RESULTS
A total of 20 patients (11 males, 9 females) were included in the present study. D-serine expression was significantly higher in the neurons and glial cells of patients with intractable epilepsy than in control individuals. The mean integrated optical density (IOD) value for the intractable epilepsy group (13.37 ± 1.88) was significantly higher than that for the control group (9.27 ± 0.62, p < 0.05). The mean absorbance value of the NMDA receptor 1 protein strip obtained from intractable epileptic patients was 0.4175 ± 0.2321, which was significantly higher than the value of 0.2402 ± 0.1458 for the control group (p < 0.05).
CONCLUSION
D-serine and NMDA receptor 1 expressions increased significantly in patients with intractable epilepsy compared with control patients. Therefore, the D-serine signaling pathway may represent a potential neurochemical target for epilepsy treatment.
Topics: Adult; Drug Resistant Epilepsy; Female; Gene Expression; Humans; Male; Middle Aged; Receptors, N-Methyl-D-Aspartate; Serine; Temporal Lobe
PubMed: 33491170
DOI: 10.5137/1019-5149.JTN.28138-19.2