scholarly journals NMDA Receptors Subunits, Medical Conditions Involved in, and Their Roles as Drug Targets

2020 ◽  
Vol 2 (4) ◽  
pp. 293-296
Author(s):  
Mohamed Omer ◽  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Drug Targets ◽  
Psychotic Disorders ◽  
Camp Response Element Binding ◽  
D1 Receptors ◽  
Ionotropic Receptor ◽  
Learning Abilities ◽  
Calcium Permeability ◽  
The 1960S

In the 1960s, Jeff Watkins and colleagues discovered N-methyl-d-aspartate (NMDA) receptors, and since then, it has been a pharmacodynamic target for many neurological and psychiatric drugs. NMDA is a glutamate receptor and ion channel protein located in nerve cells. There are many subunits for the NMDA receptor. They are all working together in a harmonic pattern to regulate the calcium permeability and the voltage-dependent sensitivity to magnesium influenced by the binding of glutamate as a neurotransmitter. In this paper, a light will be shed on glutamate ionotropic receptor NMDA subunits. There are several names for the GRIN gene, such as GluN. It is proven that GRIN has a significant influence on memory and learning abilities. Interestingly, part of how GRIN executes its function by interacting with other receptors. For example, GRIN counteracts the role of the cAMP response element-binding protein (CREP) receptor, while its function modulated by dopamine D1 receptors. Therefore, Hypo-functioning and mutation of this gene play a pivotal role in developing neurodevelopmental disorders wither it was with or without hyperkinetic movements and with and without seizures, besides several psychotic disorders such as schizophrenia. Hence, NMDA receptors subunits have been a target for therapeutic development for the last years. With the advancements in the genetic and genomic science, investigators are trying to find the alternative splicing of GRIN, understanding location and the distribution of NMDA subunits with deeper lucidity than it is currently. However, that is faced by some challenges. Modifying the NMDA receptor subunits to treat one condition can lead to potential harm effect in another condition because, sometimes, NMDA works complicatedly inversely with many other receptors and neurotransmitters, which will have an impact on the investigators to find the appropriate way to cause no harm.

Direct interactions between NMDA and D1 receptors: a tale of tails

2004 ◽  
Vol 32 (6) ◽  
pp. 1032-1036 ◽  
Author(s):  
F.J.S. Lee ◽  
F. Liu
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Neuronal Development ◽  
Direct Interaction ◽  
Complex Interaction ◽  
D1 Receptors ◽  
Functional Interaction ◽  
Disease States ◽  
C Terminus ◽  
Glutamatergic Pathways

Considerable evidence has accumulated describing a complex interaction between the dopaminergic and glutamatergic pathways. Efforts to describe the mechanisms underlying this complex interaction have implicated a functional interaction between dopamine and glutamate receptors. Classically, the interaction between D1 and NMDA (N-methyl-D-aspartate) receptors has been proposed to involve the activation of second-messenger signalling cascades after receptor stimulation. However, in recent years, another paradigm has emerged which involves the direct interaction between D1 and NMDA receptors. The physical association between D1 and NMDA receptors is unique in that two different regions of the D1 C-terminus are able to couple specifically and physically with two different NMDA subunits. The selective modulation of multiple NMDA receptor-mediated functions by direct interactions with D1 receptors may form a new avenue to identify specific targets for therapeutics to modulate NMDA receptor-governed synaptic plasticity, neuronal development and disease states.

scholarly journals Specific Assembly with the NMDA Receptor 3B Subunit Controls Surface Expression and Calcium Permeability of NMDA Receptors

2003 ◽  
Vol 23 (31) ◽  
pp. 10064-10073 ◽  
Author(s):  
Keiko Matsuda ◽  
Matt Fletcher ◽  
Yoshinori Kamiya ◽  
Michisuke Yuzaki
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Surface Expression ◽  
Calcium Permeability

Electroacupuncture ameliorates CUMS-induced depression-like behavior: involvement of the glutamatergic system and apoptosis in rats

2020 ◽  
Vol 23 ◽  
Author(s):  
Qin Guo ◽  
Xian-Ming Lin ◽  
Zhong Di ◽  
Quan-Ai Zhang ◽  
Shuo Jiang
Keyword(s):  
Nmda Receptor ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Sucrose Preference ◽  
Expression Level ◽  
Receptor Subunit ◽  
Glutamatergic System ◽  
Ionotropic Receptor ◽  
Nmda Receptor Subunit ◽  
Expression Levels

Background: Converging evidence indicates that glutamatergic system and glia are directly implicated in the pathophysiology of depression. Clinical studies indicate that electroacupuncture (EA) has antidepressant-like effect with low side effects for depression. However, the underlying antidepressant mechanism of acupuncture remains obscure. Methods: Chronic unpredictable mild stress (CUMS)-induced depressive rats were used to induce depressive-like behavior, and evaluated by the weight change, open field test, sucrose preference test, and novelty suppressed feeding test. EA, NMDA receptor subunit 2A antagonist (NR2A RA) or NMDA receptor subunit 2B antagonist (NR2B RA) was used for comparison. High performance liquid chromatography (HPLC) was performed to detect the content of hippocampal glutamate, while western blot for the hippocampal protein expression levels of calcium/calmodulin-dependent protein kinase II (CaMKII), Bax, caspase 3 and B-cell lymphoma-2 (Bcl-2). The distribution of glutamate ionotropic receptor NMDA type subunit 2A (NR2A), neuronal nuclear protein (NeuN), glutamate ionotropic receptor NMDA type subunit 2B (NR2B) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence. Results: Significant depression behavior (reduced body weight and sucrose preference, increased feeding and immobility time) was produced in CUMS-induced depressive rats, which was reversed significantly by EA. EA decreased hippocampal glutamate level. EA led to a significant decrease in expression levels of Bax, caspase 3 and CaMKⅡ accompanied by increased Bcl-2 expression level. Furthermore, EA significantly increased NR2A expression level as well as decreased NR2B expression level in hippocampus. Conclusion: EA ameliorated depression-like behavior in CUMS rats, which might be mediated, at least in part, by regulating the glutamate, NMDA receptors and apoptosis in the hippocampus.

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Zahra Lorigooini ◽  
Ali Nouri ◽  
Faezeh mottaghinia ◽  
Shima Balali-Dehkordi ◽  
Elham Bijad ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Mouse Model ◽  
Ferulic Acid ◽  
Nmda Receptors ◽  
Effective Dose ◽  
Life Stress ◽  
Receptor Agonist ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Central Zone

AbstractBackgroundExperiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors.MethodsMice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus.ResultsFindings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid.ConclusionsIn deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests.

Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).

1995 ◽  
Vol 198 (7) ◽  
pp. 1621-1628 ◽  
Author(s):  
L T Buck ◽  
P E Bickler
Keyword(s):  
Cerebral Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Control Level ◽  
Chrysemys Picta ◽  
Receptor Modulation ◽  
A1 Receptor ◽  
Excitatory Neurotransmission ◽  
Similar Decrease

Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.

Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes

1990 ◽  
Vol 63 (5) ◽  
pp. 1148-1168 ◽  
Author(s):  
W. R. Holmes ◽  
W. B. Levy
Keyword(s):  
Experimental Data ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Dendritic Spine ◽  
Long Term Potentiation ◽  
Input Frequency ◽  
Spine Head ◽  
Term Potentiation ◽  
Concentration Changes

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of N-methyl-D-aspartate receptors in the pontine pneumotaxic mechanism in the cat

1994 ◽  
Vol 76 (3) ◽  
pp. 1138-1143 ◽  
Author(s):  
L. Ling ◽  
D. R. Karius ◽  
D. F. Speck
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Partial Recovery ◽  
Inspiratory Time ◽  
Systemic Injection ◽  
Lung Inflation ◽  
Mk 801 ◽  
Efferent Limb ◽  
Adult Cats

Systemic injection of MK-801, an N-methyl-D-aspartate (NMDA) receptor-associated channel blocker, induces an apneusis in vagotomized cats similar to that produced by pontine respiratory group (PRG) lesions, suggesting the possible involvement of NMDA receptors in the pontine pneumotaxic mechanism. Previous results from our laboratory indicate that the efferent limb of the pontine pneumotaxic mechanism is unlikely to require NMDA receptor-mediated neurotransmission. Therefore, the present study examined the potential involvement of PRG NMDA receptors in the pontine pneumotaxic mechanism. Experiments were conducted in decerebrate, paralyzed, and ventilated adult cats. The effects on inspiratory time (TI) of MK-801 microinjection into PRG were tested in 12 cats. Pressure microinjection of MK-801 (15 mM, 80–3,000 nl) significantly prolonged TI in all animals when lung inflation was withheld. TI progressively increased in most animals for > or = 30 min. After this period, partial recovery of the effect occurred in eight cats as TI shortened toward predrug levels. In three animals, microinjection of MK-801 induced a complete apneusis in the absence of lung inflation from which there was no detectable recovery. Microinjections into regions approximately 2 mm distant from PRG produced little or no effect. These results provide evidence that NMDA receptors located in the region of PRG play an important functional role in the control of the breathing cycle.

A Fast Synaptic Potential Mediated by NMDA and Non-NMDA Receptors

1997 ◽  
Vol 78 (5) ◽  
pp. 2693-2706 ◽  
Author(s):  
Laura R. Wolszon ◽  
Alberto E. Pereda ◽  
Donald S. Faber
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Resting Potential ◽  
Repetitive Firing ◽  
Physiological Data ◽  
Receptor Subtypes ◽  
Excitatory Postsynaptic Potential ◽  
Synaptic Potential ◽  
Synaptic Currents ◽  
Fast Kinetics

Wolszon, Laura R., Alberto E. Pereda, and Donald S. Faber. A fast synaptic potential mediated by NMDA and non-NMDA receptors. J. Neurophysiol. 78: 2693–2706, 1997. Excitatory synaptic transmission in the CNS often is mediated by two kinetically distinct glutamate receptor subtypes that frequently are colocalized, the N-methyl-d-aspartate (NMDA) and non-NMDA receptors. Their synaptic currents are typically very slow and very fast, respectively. We examined the pharmacological and physiological properties of chemical excitatory transmission at the mixed electrical and chemical synapses between auditory afferents and the goldfish Mauthner cell, in vivo. Previous physiological data have suggested the involvement of glutamate receptors in this fast excitatory postsynaptic potential (EPSP), the chemical component of which decays with a time constant of <2 ms. We demonstrate here that the pharmacological and voltage-dependent characteristics of the synaptic currents are consistent with glutamatergic transmission and that both NMDA and non-NMDA receptors are involved. The two components surprisingly exhibit quite similar kinetics even at resting potential, with the NMDA response being only slightly slower. Due to its fast kinetics and characteristic voltage dependence, NMDA receptor-mediated transmission at these first-order synapses contributes significantly to paired pulse and frequency-dependent facilitation of successive fast EPSPs during high-frequency repetitive firing, a presynaptic impulse pattern that induces activity-dependent homosynaptic changes in both electrical and chemical transmission. Thus NMDA receptor kinetics in this intact preparation are suited to its functional requirements, namely speed of information transmission and the ability to trigger changes in synaptic efficacy.

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