scholarly journals Possible Role of N-Methyl-D-Aspartate Receptors in Physiology and Pathophysiology of Cardiovascular System

2019 ◽  
Vol 20 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Ivan Srejovic ◽  
Vladimir Jakovljevic ◽  
Vladimir Zivkovic ◽  
Dragan Djuric
Keyword(s):  
Nmda Receptors ◽  
Cardiovascular System ◽  
Ampa Receptors ◽  
Heart Function ◽  
Cell Types ◽  
Receptor Activation ◽  
Simultaneous Action ◽  
Cardiovascular Disorders ◽  
Voltage Dependent

Abstract N-methyl-D-aspartate (NMDA) receptors belong to ionotropic glutamate receptor family, together with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainite receptors and δ-receptors. All of these receptors are tetramers composed of four subunits. NMDA receptors have several unique features in relation to other ionotropic glutamate receptors: requirement for simultaneous action of two coagonists, glutamate and glycine; dual control of receptor activation, ligand-dependent (by glutamate and glycine) and voltage-dependent (Mg2+ block) control; and influx of considerable amounts of Ca2+ following receptor activation. Increasing number of researches deals with physiological and pathophysiological roles of NMDA receptors outside of nerve tissues, especially in the cardiovascular system. NMDA receptors are found in all cell types represented in cardiovascular system, and their overstimulation in pathological conditions, such as hyperhomocysteinemia, is related to a range of cardiovascular disorders. On the other hand we demonstrated that blockade of NMDA receptors depresses heart function. There is a need for the intensive study of NMDA receptor in cardiovascular system as potential theraputical target both in prevention and treatment of cardiovascular disorders.

Ifenprodil reduces excitatory synaptic transmission by blocking presynaptic P/Q type calcium channels

2012 ◽  
Vol 107 (6) ◽  
pp. 1571-1575 ◽  
Author(s):  
Andrew J. Delaney ◽  
John M. Power ◽  
Pankaj Sah
Keyword(s):  
Calcium Channels ◽  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Basolateral Amygdala ◽  
Excitatory Transmission ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
P Type ◽  
Selective Blocker

Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC50 of ∼10 μM and is fully occluded by the P/Q type calcium channel blocker ω-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels.

Analysis of the Role of Inhibition in Shaping Responses to Sinusoidally Amplitude-Modulated Signals in the Inferior Colliculus

1998 ◽  
Vol 80 (4) ◽  
pp. 1686-1701 ◽  
Author(s):  
R. Michael Burger ◽  
George D. Pollak
Keyword(s):  
Nmda Receptors ◽  
Inferior Colliculus ◽  
Ampa Receptors ◽  
Phase Locking ◽  
Receptor Blocker ◽  
Response Property ◽  
Medial Superior Olive ◽  
Competitive Antagonist ◽  
Modulated Signals

Burger, R. Michael and George D. Pollak. Analysis of the role of inhibition in shaping responses to sinusoidally amplitude-modulated signals in the inferior colliculus. J. Neurophysiol. 80: 1686–1701, 1998. Neurons in the central nucleus of the inferior colliculus (ICc) typically respond with phase-locked discharges to low rates of sinusoidal amplitude-modulated (SAM) signals and fail to phase-lock to higher SAM rates. Previous studies have shown that comparable phase-locking to SAM occurs in the dorsal nucleus of the lateral lemniscus (DNLL) and medial superior olive (MSO) of the mustache bat. The studies of MSO and DNLL also showed that the restricted phase-locking to low SAM rates is created by the coincidence of phase-locked excitatory and inhibitory inputs that have slightly different latencies. Here we tested the hypothesis that responses to SAM in the mustache bat IC are shaped by the same mechanism that shapes responses to SAM in the two lower nuclei. We recorded responses from ICc neurons evoked by SAM signals before and during the iontophoretic application of several pharmacological agents: bicuculline, a competitive antagonist for γ-aminobutyric acid-A (GABAA) receptors; strychnine, a competitive antagonist for glycine receptors; the GABAB receptor blocker, phaclofen, and the N-methyl-d-aspartate (NMDA) receptor blocker, (−)-2-amino-5-phosphonopentanoic acid (AP5). The hypothesis that inhibition shapes responses to SAM signals in the ICc was not confirmed. In >90% of the ICc neurons tested, the range of SAM rates to which they phase-locked was unchanged after blocking inhibition with bicuculline, strychnine or phaclofen, applied either individually or in combination. We also considered the possibility that faster α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors follow high temporal rates of incoming excitation but that the slower NMDA receptors could follow only lower rates. Thus at higher SAM rates, NMDA receptors might generate a sustained excitation that “smears” the phase-locked excitation generated by the AMPA receptors. The NMDA hypothesis, like the inhibition hypothesis, was also not confirmed. In none of the cells that we tested did the application of AP5 by itself, or in combination with bicuculline, cause an increase in the range of SAM rates that evoked phase-locking. These results illustrate that the same response property, phase-locking restricted to low SAM rates, is formed in more than one way in the auditory brain stem. In the MSO and DNLL, the mechanism is coincidence of phase-locked excitation and inhibition, whereas in ICc the same response feature is formed by a different but unknown mechanism.

Autophagy in health and disease: focus on the cardiovascular system

2017 ◽  
Vol 61 (6) ◽  
pp. 721-732 ◽  
Author(s):  
Jeanne Mialet-Perez ◽  
Cécile Vindis
Keyword(s):  
Heart Failure ◽  
Cardiovascular System ◽  
Crucial Role ◽  
Current Knowledge ◽  
Cardiovascular Disorders ◽  
Health And Disease ◽  
And Function ◽  
Autophagy Activity ◽  
Disease Focus

Autophagy is a highly conserved mechanism of lysosome-mediated protein and organelle degradation that plays a crucial role in maintaining cellular homeostasis. In the last few years, specific functions for autophagy have been identified in many tissues and organs. In the cardiovascular system, autophagy appears to be essential to heart and vessel homeostasis and function; however defective or excessive autophagy activity seems to contribute to major cardiovascular disorders including heart failure (HF) or atherosclerosis. Here, we review the current knowledge on the role of cardiovascular autophagy in physiological and pathophysiological conditions.

Distribution, Density, and Clustering of Functional Glutamate Receptors Before and After Synaptogenesis in Hippocampal Neurons

2000 ◽  
Vol 84 (3) ◽  
pp. 1573-1587 ◽  
Author(s):  
Jeffrey R. Cottrell ◽  
Gilles R. Dubé ◽  
Christophe Egles ◽  
Guosong Liu
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Time Course ◽  
Synapse Formation ◽  
Receptor Activation ◽  
Receptor Density

Postsynaptic differentiation during glutamatergic synapse formation is poorly understood. Using a novel biophysical approach, we have investigated the distribution and density of functional glutamate receptors and characterized their clustering during synaptogenesis in cultured hippocampal neurons. We found that functional α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors are evenly distributed in the dendritic membrane before synaptogenesis with an estimated density of 3 receptors/μm2. Following synaptogenesis, functional AMPA and NMDA receptors are clustered at synapses with a density estimated to be on the order of 104 receptors/μm2, which corresponds to ∼400 receptors/synapse. Meanwhile there is no reduction in the extrasynaptic receptor density, which indicates that the aggregation of the existing pool of receptors is not the primary mechanism of glutamate receptor clustering. Furthermore our data suggest that the ratio of AMPA to NMDA receptor density may be regulated to be close to one in all dendritic locations. We also demonstrate that synaptic AMPA and NMDA receptor clusters form with a similar time course during synaptogenesis and that functional AMPA receptors cluster independently of activity and glutamate receptor activation, including following the deletion of the NMDA receptor NR1 subunit. Thus glutamate receptor activation is not necessary for the insertion, clustering, and activation of functional AMPA receptors during synapse formation, and this process is likely controlled by an activity-independent signal.

scholarly journals Potentiation of Synaptic AMPA Receptors Induced by the Deletion of NMDA Receptors Requires the GluA2 Subunit

2011 ◽  
Vol 105 (2) ◽  
pp. 923-928 ◽  
Author(s):  
Wei Lu ◽  
John A. Gray ◽  
Adam J. Granger ◽  
Matthew J. During ◽  
Roger A. Nicoll
Keyword(s):  
Nmda Receptors ◽  
Single Cell ◽  
Ampa Receptors ◽  
Substantial Evidence ◽  
Ampar Trafficking

Deletion of N-methyl-d-aspartate receptors (NMDARs) early in development results in an increase in the number of synaptic AMPA receptors (AMPARs), suggesting a role for NMDARs in negatively regulating AMPAR trafficking at developing synapses. Substantial evidence has shown that AMPAR subunits function differentially in AMPAR trafficking. However, the role of AMPAR subunits in the enhancement of AMPARs following NMDAR ablation remains unknown. We have now performed single-cell genetic deletions in double-floxed mice in which the deletion of GluN1 is combined with the deletion of GluA1 or GluA2. We find that the AMPAR enhancement following NMDAR deletion requires the GluA2 subunit, but not the GluA1 subunit, indicating a key role for GluA2 in the regulation of AMPAR trafficking in developing synapses.

Dopaminergic Modulation of NMDA-Induced Whole Cell Currents in Neostriatal Neurons in Slices: Contribution of Calcium Conductances

1998 ◽  
Vol 79 (1) ◽  
pp. 82-94 ◽  
Author(s):  
Carlos Cepeda ◽  
Christopher S. Colwell ◽  
Jason N. Itri ◽  
Scott H. Chandler ◽  
Michael S. Levine
Keyword(s):  
Nmda Receptors ◽  
Receptor Activation ◽  
Membrane Currents ◽  
Channel Blockers ◽  
Complex Interplay ◽  
Whole Cell ◽  
Dopaminergic Modulation ◽  
Voltage Dependent ◽  
Induced Currents ◽  
Nmda Receptor Activation

Cepeda, Carlos, Christopher S. Colwell, Jason N. Itri, Scott H. Chandler, and Michael S. Levine. Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices: contribution of calcium conductances. J. Neurophysiol. 79: 82–94, 1998. The present experiments were designed to examine dopamine (DA) modulation of whole cell currents mediated by activation of N-methyl-d-aspartate (NMDA) receptors in visualized neostriatal neurons in slices. First, we assessed the ability of DA, D1 and D2 receptor agonists to modulate membrane currents induced by activation of NMDA receptors. The results of these experiments demonstrated that DA potentiated NMDA-induced currents in medium-sized neostriatal neurons. Potentiation of NMDA currents occurred at three different holding potentials, although it was more pronounced at −30 mV. It was mediated by D1 receptors, because it was mimicked by D1 agonists and blocked by exposure to a D1 antagonist. Activation of D2 receptors produced inconsistent effects on NMDA-induced membrane currents. Either decreases, increases, or no effects on NMDA currents occurred. Second, we examined the contributions of intrinsic, voltage-dependent conductances to DA potentiation of NMDA currents. Blockade of K+ conductances did not prevent DA enhancement of NMDA currents. However, voltage-activated Ca2+ conductances provided a major contribution to DA modulation. The dihydropyridine L-type Ca2+ channel blockers, nifedipine, and methoxyverapamil (D−600), markedly reduced but did not totally eliminate the ability of DA to modulate NMDA currents. The D1 receptor agonist SKF 38393 also enhanced Ba2+ currents in neostriatal neurons. Together, these findings provide evidence for a complex interplay between DA, NMDA receptor activation and dihydropyridine-sensitive Ca2+ conductances in controlling responsiveness of neostriatal medium-sized neurons.

Role of AMPA Receptor Desensitization and the Side Effects of a DMSO Vehicle on Reticulospinal EPSPs and Locomotor Activity

2005 ◽  
Vol 94 (6) ◽  
pp. 3951-3960 ◽  
Author(s):  
Nataliya A. Tsvyetlynska ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Nmda Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Pattern Generation ◽  
Network Activity ◽  
Excitatory Postsynaptic Potential ◽  
Receptor Desensitization ◽  
Neuronal Network Activity ◽  
The Brain

Activation of the vertebrate locomotor network is mediated by glutamatergic synaptic drive, normally initiated by the brain stem. Previous investigations have studied the role of glutamate receptors, especially NMDA receptors, in generating and regulating locomotor pattern generation. Few studies, however, have focused on the role of AMPA receptors in shaping network activity, especially with regard to their rapid desensitization. It is important to determine whether AMPA receptor desensitization plays a role in regulating neuronal network activity. We examined this question on both the network and synaptic levels in the lamprey ( Lampetra fluviatilis) spinal cord using a selective and potent inhibitor of AMPA receptor desensitization, cyclothiazide (CTZ). The solvent dimethyl sulfoxide (DMSO) is commonly used to dissolve this drug, as well as many others. Unexpectedly, the vehicle alone already at 0.02%, but not at 0.01%, caused significant increases in excitatory postsynaptic potential (EPSP) amplitudes and NMDA-induced locomotor frequency. The results indicate that DMSO may have a profound influence when used ≥0.02%, a concentration 10–50 times less than that most commonly used. Subsequently we applied CTZ concentrations ≤10 μM (DMSO ≤0.01%). CTZ (1.25–5 μM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors. From the effects of CTZ it is apparent that AMPA receptor desensitization plays an important role in determining locomotor frequency and that this is likely a result of its limiting function on AMPA receptor–mediated EPSPs.

scholarly journals The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation

PLoS ONE ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. e0147293 ◽  
Author(s):  
Alexandre A. Hoeller ◽  
Ana Paula R. Costa ◽  
Maíra A. Bicca ◽  
Filipe C. Matheus ◽  
Gilliard Lach ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Muscarinic Receptor ◽  
Emotional Responses ◽  
Receptor Activation

scholarly journals The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

2021 ◽  
Vol 22 (4) ◽  
pp. 2194
Author(s):  
Yi-Zhen Wang ◽  
Ebenezeri Erasto Ngowi ◽  
Di Wang ◽  
Hui-Wen Qi ◽  
Mi-Rong Jing ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Cell Types ◽  
Special Focus ◽  
Protective Effects ◽  
Improve Heart Function ◽  
Different Cell Types

Hydrogen sulfide (H2S) has long been considered as a toxic gas, but as research progressed, the idea has been updated and it has now been shown to have potent protective effects at reasonable concentrations. H2S is an endogenous gas signaling molecule in mammals and is produced by specific enzymes in different cell types. An increasing number of studies indicate that H2S plays an important role in cardiovascular homeostasis, and in most cases, H2S has been reported to be downregulated in cardiovascular diseases (CVDs). Similarly, in preclinical studies, H2S has been shown to prevent CVDs and improve heart function after heart failure. Recently, many H2S donors have been synthesized and tested in cellular and animal models. Moreover, numerous molecular mechanisms have been proposed to demonstrate the effects of these donors. In this review, we will provide an update on the role of H2S in cardiovascular activities and its involvement in pathological states, with a special focus on the roles of exogenous H2S in cardiac protection.

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