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A Neurochemical Approach to Elucidate Metabotropic vs. Ionotropic Glutamate Receptor Activities in Rat Hippocampal Slices
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Darryle D. Schoepp, Manisha A. Desai
As discussed above, a characteristic of AMPA receptors that is not shared by other ionotropic glutamate receptors or metabotropic glutamate receptors is their modulation by cyclothiazide. Thus, the use of cyclothiazide in biochemical assays such as measurement of 3H-NE release can aid in determining which agonist responses are selectively mediated by AMPA receptors as opposed to kainate and NMDA receptors. For instance, Figure 2 shows the effects of cyclothiazide on 3H-NE release in the presence of the five glutamate receptor agonists described in Figure 1. Consistent with the effects of cyclothiazide being selective for AMPA receptors, 3H-NE release is enhanced in response to AMPA, kainate, and quisqualate, but not to NMDA or 1S,3R-ACPD, as compared to Figure 1. Thus, NMDA receptors and metabotropic glutamate receptors are not positively modulated by cyclothiazide. Again, the response to quisqualate, which has activity at both AMPA receptors and metabotropic glutamate receptors, is enhanced by cyclothiazide. This supports the hypothesis that 3H-NE release by these compounds is mediated by the AMPA subtype of ionotropic glutamate receptors, and that this assay system is useful for pharmacological studies with compounds having either competitive or allosteric mechanisms of drug interaction.
Classifications
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
Intermediate-actingCyclothiazideMethylclothiazideQuinethazoneTrichlormethiazide
Interleukin-10 restores glutamate receptor-mediated Ca2+-signaling in brain circuits under loss of Sip1 transcription factor
Published in International Journal of Neuroscience, 2021
Maria V. Turovskaya, Ekaterina A. Epifanova, Victor S. Tarabykin, Alexei A. Babaev, Egor A. Turovsky
The second excitatory ionotropic glutamate receptor is the AMPA receptor which activity in Sip1fl/fl neurons grown with the addition of IL-10 also significantly increases compared to Sip1fl/fl neurons grown under standard conditions. This effect can be judged by an increase in amplitude Ca2+ responses to the application of increasing concentrations of the selective agonist fluorowillardiine, added in the presence of 5 μM AMPA receptor desensitization inhibitor cyclothiazide (Figure 3(B), light curve, Sip1fl/fl + IL-10). In addition, Ca2+ signals in response to the agonist in neurons grown in the presence of IL-10 appear at fluorowillardiine concentrations of 0.01–0.03 μM (Figure 2(B), red line, indicated by numbers 2 and 3) while neurons grown in standard medium begin to respond with an increase in [Ca2+]i only at 0.1 μM (Figure 2(B), black line, indicated by 4).
Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis
Published in Platelets, 2021
Maggie L. Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M. Ward, James I. Hearn, Justin R. Hamilton, Anna Y. Bogdanova
Further experiments by Morrell et al. provided powerful evidence corroborating AMPAR and KAR contribution to platelet activation [18,19]. Mice given CNQX and UBP302 have longer bleeding times and are protected from arterial thrombosis in the FeCl3 mesenteric artery thrombosis model (including longer times to platelet adhesion, thrombus formation, and vessel occlusion). Similar antithrombotic effects were observed following FeCl3 induced damage in the GRIA1 and GRIK2 knockout mice [18,19]. The mechanism of AMPAR and KAR effects in platelets involves an increase in intracellular Na+ leading to membrane depolarization, consistent with their neuronal activities, but not Ca2+ influx. These properties were confirmed in platelets using fluorescent Na+-sensitive probe and electrophysiological recordings in isolated mouse megakaryocytes [18]. AMPAR and KAR currents were small but consistently recorded in the presence of cyclothiazide (an allosteric inhibitor of desensitization). Joro spider toxin that inhibits Ca2+-permeable AMPAR had no effect on platelet activation by AMPA, arguing against AMPAR-mediated Ca2+ influx in platelets [18]. Kainate was also shown to activate the p38 MAPK signaling that operates upstream of cyclooxygenase 1 (COX-1) in platelets. KAR signaling increases COX activity and production of thromboxane A2 (platelet agonist), suggesting another mechanism for platelet activation by KAR independent of platelet membrane depolarization [19].