Ionotropic Glutamate Receptors (AMPA, Kainate and NMDA 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.

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Ionotropic glutamate receptors of amacrine cells of the mouse retina

Visual Neuroscience ◽

10.1017/s0952523806231079 ◽

2006 ◽

Vol 23 (1) ◽

pp. 79-90 ◽

Cited By ~ 15

Author(s):

OLIVIA N. DUMITRESCU ◽

DARIO A. PROTTI ◽

SRIPARNA MAJUMDAR ◽

HANNS ULRICH ZEILHOFER ◽

HEINZ WÄSSLE

Keyword(s):

Nmda Receptors ◽

Glutamate Receptors ◽

Amacrine Cell ◽

Fluorescent Protein ◽

Lucifer Yellow ◽

Amacrine Cells ◽

Ionotropic Glutamate Receptors ◽

Mouse Retina ◽

Wide Field ◽

Transgenic Mouse Line

The mammalian retina contains approximately 30 different morphological types of amacrine cells, receiving glutamatergic input from bipolar cells. In this study, we combined electrophysiological and pharmacological techniques in order to study the glutamate receptors expressed by different types of amacrine cells. Whole-cell currents were recorded from amacrine cells in vertical slices of the mouse retina. During the recordings the cells were filled with Lucifer Yellow/Neurobiotin allowing classification as wide-field or narrow-field amacrine cells. Amacrine cell recordings were also carried out in a transgenic mouse line whose glycinergic amacrine cells express enhanced green fluorescent protein (EGFP). Agonist-induced currents were elicited by exogenous application of NMDA, AMPA, and kainate (KA) while holding cells at −75 mV. Using a variety of specific agonists and antagonists (NBQX, AP5, cyclothiazide, GYKI 52466, GYKI 53655, SYM 2081) responses mediated by AMPA, KA, and NMDA receptors could be dissected. All cells (n= 300) showed prominent responses to non-NMDA agonists. Some cells expressed AMPA receptors exclusively and some cells expressed KA receptors exclusively. In the majority of cells both receptor types could be identified. NMDA receptors were observed in about 75% of the wide-field amacrine cells and in less than half of the narrow-field amacrine cells. Our results confirm that different amacrine cell types express distinct sets of ionotropic glutamate receptors, which may be critical in conferring their unique temporal responses to this diverse neuronal class.

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Region-specific expression of subunits of ionotropic glutamate receptors (AMPA-type, KA-type and NMDA receptors) in the rat spinal cord with special reference to nociception

Molecular Brain Research ◽

10.1016/0169-328x(93)90183-p ◽

1993 ◽

Vol 18 (1-2) ◽

pp. 141-151 ◽

Cited By ~ 147

Author(s):

Tatsuo Furuyama ◽

Hiroshi Kiyama ◽

Kohji Sato ◽

Hwan Tae Park ◽

Hiroshi Maeno ◽

...

Keyword(s):

Spinal Cord ◽

Nmda Receptors ◽

Special Reference ◽

Glutamate Receptors ◽

Ionotropic Glutamate Receptors ◽

Rat Spinal Cord ◽

Specific Expression

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Synaptic NR2A- but not NR2B-containing NMDA receptors increase with blockade of ionotropic glutamate receptors

Frontiers in Molecular Neuroscience ◽

10.3389/neuro.02.019.2009 ◽

2009 ◽

Vol 2 ◽

Cited By ~ 14

Author(s):

Jakob von Engelhardt

Keyword(s):

Nmda Receptors ◽

Glutamate Receptors ◽

Ionotropic Glutamate Receptors

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High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors

Anesthesiology ◽

10.1097/aln.0000000000001665 ◽

2017 ◽

Vol 127 (1) ◽

pp. 89-97 ◽

Cited By ~ 4

Author(s):

Irene Lecker ◽

Dian-Shi Wang ◽

Kirusanthy Kaneshwaran ◽

C. David Mazer ◽

Beverley A. Orser

Keyword(s):

Tranexamic Acid ◽

Nmda Receptors ◽

Glutamate Receptors ◽

Hippocampal Neurons ◽

Inhibitory Concentration ◽

Cell Voltage ◽

Kainate Receptors ◽

Ionotropic Glutamate Receptors ◽

Competitive Antagonist ◽

Peripheral Tissues

Abstract Background The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors. Methods Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons. Results Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration–response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5). Conclusions Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.

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Local Ionotropic Glutamate Receptors are Required to Trigger and Sustain Ramping of Sympathetic Nerve Activity by Hypothalamic Paraventricular Nucleus TNFα

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00322.2021 ◽

2021 ◽

Author(s):

Aline A. Mourao ◽

Caroline G. Shimoura ◽

Mary Ann Andrade ◽

Tamara T. Truong ◽

Gustavo R. Pedrino ◽

...

Keyword(s):

Nmda Receptors ◽

Glutamate Receptors ◽

Paraventricular Nucleus ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Hypothalamic Paraventricular Nucleus ◽

Ionotropic Glutamate Receptors ◽

Sprague Dawley ◽

Nerve Activity ◽

Necrosis Factor Alpha

Tumor necrosis factor alpha (TNFa) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFa (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P<0.0001, n=10). Given that TNFa can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. Compared to vehicle (n=5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: NBQX, 2.48 nmol; APV, 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%) attenuated TNFα-induced SSNA ramping (n=5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P<0.0001, n=5). Whereas separate blockade of PVN AMPA or NMDA receptors (n=5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n=5) or PVN inhibition with the GABA-A receptor agonist muscimol (n=5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.

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