scholarly journals NMDA and AMPA Receptors: Development and Status Epilepticus

2013 ◽  
pp. S21-S38 ◽  
Author(s):  
E. SZCZUROWSKA ◽  
P. MAREŠ
Keyword(s):  
Status Epilepticus ◽  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Ionotropic Glutamate Receptors ◽  
Cognitive Disability ◽  
Excitatory Neurotransmitter ◽  
Functional Changes ◽  
Excitatory Neurotransmission ◽  
Intensive Investigation ◽  
High Level

Glutamate is the main excitatory neurotransmitter in the brain and ionotropic glutamate receptors mediate the majority of excitatory neurotransmission (Dingeldine et al. 1999). The high level of glutamatergic excitation allows the neonatal brain (the 2nd postnatal week in rat) to develop quickly but it also makes it highly prone to age-specific seizures that can cause lifelong neurological and cognitive disability (Haut et al. 2004). There are three types of ionotropic glutamate receptors (ligand-gated ion channels) named according to their prototypic agonists: N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) and kainate (KA). During early stages of postnatal development glutamate receptors of NMDA and AMPA type undergo intensive functional changes owing to modifications in their subunit composition (Carter et al. 1988, Watanabe et al. 1992, Monyer et al. 1994, Wenzel et al. 1997, Sun et al. 1998, Lilliu et al. 2001, Kumar et al. 2002, Matsuda et al. 2002, Wee et al. 2008, Henson et al. 2010, Pachernegg et al. 2012, Paoletti et al. 2013). Participation and role of these receptors in mechanisms of seizures and epilepsy became one of the main targets of intensive investigation (De Sarro et al. 2005, Di Maio et al. 2012, Rektor 2013). LiCl/Pilocarpine (LiCl/Pilo) induced status epilepticus is a model of severe seizures resulting in development temporal lobe epilepsy (TLE). This review will consider developmental changes and contribution of NMDA and AMPA receptors in LiCl/Pilo model of status epilepticus in immature rats.

Pharmacological characterization, localization, and regulation of ionotropic glutamate receptors in skate horizontal cells

2009 ◽  
Vol 26 (4) ◽  
pp. 375-387 ◽  
Author(s):  
MATTHEW A. KREITZER ◽  
ANDREA D. BIRNBAUM ◽  
HAOHUA QIAN ◽  
ROBERT PAUL MALCHOW
Keyword(s):  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Polyclonal Antibodies ◽  
Plexiform Layer ◽  
Cell Voltage ◽  
Horizontal Cells ◽  
Ionotropic Glutamate Receptors ◽  
Pharmacological Characterization ◽  
Excitatory Neurotransmitter

AbstractGlutamate is believed to be the primary excitatory neurotransmitter in the vertebrate retina, and its fast postsynaptic effects are elicited by activating NMDA-, kainate-, or AMPA-type glutamate receptors. We have characterized the ionotropic glutamate receptors present on retinal horizontal cells of the skate, which possess a unique all-rod retina simplifying synaptic circuitry within the outer plexiform layer (OPL). Isolated external horizontal cells were examined using whole-cell voltage-clamp techniques. Glutamate and its analogues kainate and AMPA, but not NMDA, elicited dose-dependent currents. The AMPA receptor antagonist GYKI 52466 at 100μmabolished glutamate-elicited currents. Desensitization of glutamate currents was removed upon coapplication of cyclothiazide, known to potentiate AMPA receptor responses, but not by concanavalin A, which potentiates kainate receptor responses. The dose–response curve to glutamate was significantly broader in the presence of the desensitization inhibitor cyclothiazide. Polyclonal antibodies directed against AMPA receptor subunits revealed prominent labeling of isolated external horizontal cells with the GluR2/3 and GluR4 antibodies. 1-Naphthylacetyl spermine, known to block calcium-permeable AMPA receptors, significantly reduced glutamate-gated currents of horizontal cells. Downregulation of glutamate responses was induced by increasing extracellular ion concentrations of Zn2+and H+. The present study suggests that Ca2+-permeable AMPA receptors likely play an important role in shaping the synaptic responses of skate horizontal cells and that alterations in extracellular concentrations of calcium, zinc, and hydrogen ions have the potential to regulate the strength of postsynaptic signals mediated by AMPA receptors within the OPL.

scholarly journals Gating the channel pore of ionotropic glutamate receptors with bacterial substrate binding proteins

2021 ◽  
Author(s):  
Max Bernhard ◽  
Bodo Laube
Keyword(s):  
Glutamate Receptors ◽  
Binding Proteins ◽  
Disulfide Bridge ◽  
Ionotropic Glutamate Receptors ◽  
Functional Coupling ◽  
Channel Pore ◽  
Channel Current ◽  
Binding Domains ◽  
Bacterial Binding ◽  
Excitatory Neurotransmission

AbstractTetrameric ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the mammalian central nervous system and are involved in learning, memory formation, and pathological processes. Based on structural and sequence similarities of the ligand-binding and channel domains of iGluR subunits to bacterial binding proteins and potassium channels, iGluRs are thought to have originally arisen from their fusion. Here we report the functional coupling of the bacterial ectoine binding protein EhuB to the channel pore-forming transmembrane domains of the bacterial GluR0 receptor by stabilization of dimeric binding domains. Insertion of a disulfide bridge in the dimer interface abolished desensitization of the channel current analogous to mammalian iGluRs. These results demonstrate the functional compatibility of bacterial binding proteins to the gate of the channel pore of an iGluR. Moreover, our results highlight the modular structure and crucial role of binding domain dimerization in the functional evolution of iGluRs.

scholarly journals Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

2022 ◽  
Vol 14 ◽  
Author(s):  
Shuang Chen ◽  
Da Xu ◽  
Liu Fan ◽  
Zhi Fang ◽  
Xiufeng Wang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Receptors ◽  
Neurological Disorders ◽  
Nerve Conduction ◽  
Ionotropic Glutamate Receptors ◽  
Future Studies ◽  
Excitatory Neurotransmission ◽  
The Relationship ◽  
Neuron Injury

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

scholarly journals UNDERSTANDING THE PHYSIOLOGY OF GLUTAMATE RECEPTORS BY USE OF A PROTOCOL FOR NEURONAL STAINING

2003 ◽  
Vol 27 (2) ◽  
pp. 78-85 ◽  
Author(s):  
João O. Malva ◽  
Ana P. Vieira ◽  
Catarina R. Oliveira
Keyword(s):  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Complex Analysis ◽  
Ionotropic Glutamate Receptors ◽  
Neurotransmitter Receptors ◽  
Cultured Neurons ◽  
Bright Field ◽  
Dendritic Network ◽  
Sophisticated Equipment ◽  
Bright Field Microscopy

Teaching students about the physiology of neurotransmitter receptors usually requires practical lessons with the use of sophisticated equipment and complex analysis of data. Here, we report our experience in teaching medical students with a simple, practical protocol that transforms the physiology of glutamate receptors into neuronal staining, observable under bright-field microscopy. Essentially, the students were challenged to selectively stain a subpopulation of cultured neurons expressing Ca2+-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors (a subgroup of ionotropic glutamate receptors). Neurons expressing this type of receptors were loaded with Co2+ (in substitution for Ca2+) after nondesensitizing activation of AMPA receptors. After precipitation, the Co2+ was revealed after treatment with silver. At the end of the procedure, the neurons expressing Ca2+-permeable AMPA receptors were visually identified under bright-field microscopy. The procedure allowed the visualization of the complete dendritic network of the stained neurons and allowed the students to learn very efficiently about the physiology of glutamate receptors.

scholarly journals Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission

2008 ◽  
pp. S49-S57
Author(s):  
M Sedláček ◽  
M Kořínek ◽  
M Petrovič ◽  
O Cais ◽  
E Adamusová ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Transmembrane Domain ◽  
Kainate Receptors ◽  
Ionotropic Glutamate Receptors ◽  
Extracellular Loop ◽  
Inhibitory Effects ◽  
Chimeric Receptors

Ionotropic glutamate receptors function can be affected by neurosteroids, both positively and negatively. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit composition) by pregnenolone sulphate (PS) and inhibited by pregnanolone sulphate (3alpha5betaS). While PS effect is most pronounced when its application precedes that of glutamate, 3alpha5betaS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3alpha5betaS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor molecule has not yet been identified, however, the experiments indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects respectively. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3alpha5betaS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.

scholarly journals Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

2015 ◽  
Vol 123 (6) ◽  
pp. 1383-1393 ◽  
Author(s):  
Vincent A. Jourdain ◽  
Nicolas Morin ◽  
Laurent Grégoire ◽  
Marc Morissette ◽  
Thérèse Di Paolo
Keyword(s):  
Basal Ganglia ◽  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Specific Binding ◽  
Postmortem Brain ◽  
Ionotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Levodopa Treatment ◽  
Mglu5 Receptors ◽  
Surgical Treatments

OBJECT Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. METHODS The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys. RESULTS The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor–specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor–specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. CONCLUSIONS These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control.

AMPA receptor activation of area postrema neurons

1999 ◽  
Vol 276 (2) ◽  
pp. R586-R590 ◽  
Author(s):  
Meredith Hay ◽  
Kathy A. Lindsley
Keyword(s):  
Receptor Antagonist ◽  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Area Postrema ◽  
Nmda Antagonist ◽  
Cytosolic Calcium ◽  
Receptor Activation ◽  
Ionotropic Glutamate Receptors ◽  
Maximal Response ◽  
Dose Dependent

This study reports on the effects of activation of ionotropic glutamate receptors on area postrema neuron cytosolic calcium concentration ([Ca2+]i). In 140 of 242 area postrema neurons isolated from postnatal rats, application of 100 μMl-glutamate (l-Glu) resulted in a significant increase in [Ca2+]i. The remaining neurons were unaffected. The effects ofl-Glu on area postrema [Ca2+]iwere dose dependent, with a threshold of response near 1.0 μM and maximal response near 100 μM. To determine if the response ofl-Glu in area postrema neurons was due to activation of ionotropic glutamate receptors, the effects of the broad-spectrum ionotropic glutamate receptor antagonist kynurinic acid (Kyn) was determined. Application of 1.0 mM Kyn resulted in a 62.6 ± 4% inhibition of thel-Glu-evoked response. Application of the selective N-methyl-d-aspartic acid (NMDA) antagonist 2-amino-5-phosphonopentanoic acid had no effect on the response of area postrema neurons to 100 μMl-Glu. In contrast, application of the selectivedl-α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA)/kainate receptor antagonist 6,7-dinitroquinoxaline (DNQX) effectively blocked the 100 μMl-Glu response. Application of (±)-AMPA mimicked the effects observed withl-Glu and was selectively blocked by DNQX. These results suggest thatl-Glu activation of area postrema neurons involves activation of AMPA receptors but not NMDA receptors.

scholarly journals Ionotropic glutamate receptors in the external lateral parabrachial nucleus participate in processing cardiac sympathoexcitatory reflexes

2012 ◽  
Vol 302 (7) ◽  
pp. H1444-H1453 ◽  
Author(s):  
Liang-Wu Fu ◽  
Zhi-Ling Guo ◽  
John C. Longhurst
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Repeated Administration ◽  
Parabrachial Nucleus ◽  
Ionotropic Glutamate Receptors ◽  
Reflex Responses ◽  
Lateral Parabrachial Nucleus ◽  
Artificial Cerebrospinal Fluid ◽  
Before And After

Stimulation of cardiac sympathetic afferents during myocardial ischemia with metabolites such as bradykinin (BK) evokes sympathoexcitatory reflex responses and activates neurons in the external lateral parabrachial nucleus (elPBN). The present study tested the hypothesis that this region in the pons processes sympathoexcitatory cardiac reflexes through an ionotropic glutamate receptor mechanism. The ischemic metabolite BK (0.1–1 μg) was injected into the pericardial space of anesthetized and bilaterally vagotomized or intact cats. Hemodynamic and renal sympathetic nerve activity (RSNA) responses to repeated administration of BK before and after unilateral 50-nl microinjections of kynurenic acid (Kyn; 25 mM), 2-amino-5-phosphonopentanoic acid (AP5; 25 mM), and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol(F)quinoxaline (NBQX; 10 mM) into the elPBN were recorded. Intrapericardial BK evoked significant increases in mean arterial pressure (MAP) and RSNA in seven vagotomized cats. After blockade of glutamate receptors with the nonselective glutamate receptor antagonist Kyn, the BK-evoked reflex increases in MAP (50 ± 6 vs. 29 ± 2 mmHg) and RSNA (59 ± 8.6 vs. 29 ± 4.7%, before vs. after) were significantly attenuated. The BK-evoked responses returned to pre-Kyn levels 85 min after the application of Kyn. Similarly, BK-evoked reflex responses were reversibly attenuated by blockade of glutamate N-methyl-d-aspartate (NMDA) receptors with AP5 ( n = 5) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with NBQX ( n = 5). In contrast, we observed that the repetitive administration of BK evoked consistent reflex responses including MAP and RSNA before and after microinjection of 50 nl of the artificial cerebrospinal fluid vehicle into the elPBN in five animals. Microinjection of glutamate receptor antagonists into regions outside the elPBN did not alter BK-induced reflex responses. Microinjection of Kyn into the elPBN reversibly attenuated BK-induced reflex responses in four vagus intact animals. These data are the first to show that NMDA and AMPA ionotropic glutamate receptors in the elPBN play an important role in processing cardiac excitatory reflex responses.

scholarly journals GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

2016 ◽  
Vol 113 (38) ◽  
pp. E5645-E5654 ◽  
Author(s):  
Xue-Yan He ◽  
Yan-Jun Li ◽  
Chakrapani Kalyanaraman ◽  
Li-Li Qiu ◽  
Chen Chen ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Crystal Structures ◽  
Signal Peptide ◽  
Ampa Receptors ◽  
Critical Role ◽  
Cross Linking ◽  
Signal Peptides ◽  
Amino Terminal ◽  
Excitatory Neurotransmission ◽  
The Brain

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in full-length GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1–2–1–2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.

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