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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
AMPA receptors were previously referred to as quisqualate receptors. However, this terminology is no longer used. Unlike AMPA, quisqualate also possesses a high affinity for metabotropic glutamate receptors.4 Receptor subunit proteins that correspond to AMPA receptors have now been cloned. AMPA receptor proteins include GluRl, GluR2, GluR3, and GluR4.3 It is likely that the AMPA receptor complexes throughout the CNS are composed of combinations of these subunit proteins. The agonist kainate selectively binds to and activates another population of glutamate receptors. These kainate receptors are composed of subunit proteins that include GluR5, GluR6, GluR7, KA1, and KA2.3 Kainate receptors composed of these subunit proteins are relatively insensitive to AMPA.9 Nevertheless, kainate can also activate AMPA receptors, and an agonist that clearly distinguishes these two receptor types in situ is not known. However, recently it has been shown that AMPA receptors can be clearly distinguished from “kainate” receptors using agents that act on modulatory sites on the AMPA receptor complexes. The compound cyclothiazide selectively acts on cloned and in situ AMPA-sensitive receptors to enhance agonist-induced currents through an allosteric mechanism.10–12 Cyclothiazide has no effects on kainate-induced currents using cells expressing kainate-sensitive AMPA-insensitive subunit proteins.12 Thus, this agent offers a way to distinguish whether the effects of kainate are mediated by AMPA- or kainate-selective receptors in situ. AMPA/kainate receptor responses can also be inhibited by the benzodiazepine derivative GYKI 52466.13 Like cyclothiazide, this compound probably acts at an allosteric site on the AMPA receptor complex to reduce receptor-mediated ion flow.14,15 A number of competitive AMPA receptor antagonists that compete at the glutamate recognition site of the receptor, but have no intrinsic activity, are also known. These include 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX)16 and LY215490.17 Thus, there are various ways to positively and negatively influence AMPA receptor activity, and each of these approaches offers starting points for rational drug design.
Human Coronaviruses Respiratory Pathogens Revisited as Infectious Neuroinvasive, Neurotropic, and Neurovirulent Agents
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Marc Desforges, Dominique J. Favreau, Élodie Brison, Jessica Desjardins, Mathieu Meessen-Pinard, Hélène Jacomy, Pierre J. Talbot
Neurotransmission between adjacent neurons is an essential process in the CNS where glutamate is the major excitatory neurotransmitter involved in several functions. In physiological conditions, glutamate is synthesized by neurons and released in the synaptic cleft. Two types of ionotropic transmembrane receptors for glutamate that mediates synaptic transmission exist in the central nervous sytem (CNS). The glutamate excitotoxicity was shown to be involved in several viral infections such as WNV, Sindbis virus, JEV, HIV and HSV (Blakely et al. 2009; Carmen et al. 2009; Golembewski et al. 2007; Mishra et al. 2007; Haughey et al. 2001). The loss of neuronal subpopulations in the brain during HIV dementia was also related to an indirect mechanism conjugating glial activation, cytokines released and excitotoxic transmission (Alirezaei et al. 2008; Masliah et al. 1996). Using a mouse model, we recently showed that during infection by HCoV-0C43, hippocampal neurons died in part by this glutamate excitotoxicity as they were partially protected from degeneration in mice that were treated with the AMPA receptor antagonist (GYKI-52466) (Brison et al. 2011). Therefore, HCoV infection of the CNS may also involve excito-toxicity, which could account for the neurological disease associated with the infection. From a scientific point of view, it is interesting to note that this process has over the years been associated with diverse human neurological diseases such as Huntington’s disease, AD, PD, and ALS, as well as MS (Lau and Tymianski 2010; Haeberlein and Lipton 2009). first is named the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPAr) and the second N-methyl-n-aspartate receptor (NMDAr) (reviewed by Watkins and Jane 2006). Activation of the downstream AMPA receptor allows the entry of sodium ions in the postsynaptic neuron in order to mediate the neuronal membrane depolarization. Using another type of glutamate receptor, called the glutamate-transporter 1 (GLT-1), astrocytic cells clear the excess of extracellular glutamate in the synaptic cleft by uptake through special receptors that are high-affinity tansporters of glutamate (reviewed by Kuzmiski and Bains 2010). A disruption of glutamate homeostasis may induce neuronal degeneration and eventual cell death by an excitotoxic process (Mark et al. 2001), which is an excessive stimulation by the neurotransmitter glutamate on its specific receptors (AMPAr and NMDAr) (Olney 1969; Figure 5.6), This is of particular interest considering that since then,
Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems
Published in Psychiatry and Clinical Psychopharmacology, 2019
Meral Erdinc, Emre Uyar, Ilker Kelle, Hasan Akkoc
In the present study, GYKI-52466, a non-competitive AMPA receptor antagonist, exhibited antinociceptive effects while a combination with ketamine did not make a significant difference. An increasing body of evidence suggests that glutamatergic mechanisms and glutamate receptors are involved in the regulation of pain, i.e. pain transmission [16]. Studies implied that glutamate acts as a nociceptive neurotransmitter. In animal and human studies, it is suggested that AMPA receptor agonist administration increases pain [17] while antagonist drugs were reported to produce specific analgesic effects [18]. Studies reported that ketamine administration increases glutamatergic transmission on AMPA receptors [19]. Ketamine-induced antinociception that increases AMPA receptor activity indicates that different mechanisms are involved in antinociceptive effects of ketamine and GYKI-52466.
ALSUntangled 48: Perampanel (Fycompa)
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019
Drugs that block AMPA-type glutamate receptors, i.e. antagonists, have been tested in several ALS pre-clinical models. The AMPA antagonist drugs talampanel, GYKI-52466, and ZK 187638 are thought to work via the same mechanism as perampanel, i.e. decreasing the AMPA receptor’s ability to excite neurons (13,24,25). GYKI-52466 was shown to be protective in a motor neuron cell model of glutamate excitotoxicity (26) and extended survival in a small unpublished study of mutant SOD1 mice (Rothstein cited in 18). ZK 187638 was also shown to increase survival time in the mutant SOD1 mouse model (27). Talampanel was shown to have some benefits on the pathology in mutant SOD1 mice (28), but survival testing results have not been published. Other AMPA antagonists, e.g. RPR-1199900 and NBQX, directly inhibit glutamate from binding the AMPA receptor which leads to less neuron excitation (29,30). These two drugs have also been shown to improve survival time in the mutant SOD1 mouse model (29,31).