Ionotropic and metabotropic glutamate receptor structure and pharmacology

Kew, James N.C.; Kemp, John A.

doi:10.1007/s00213-005-2200-z

Cited by 687 publications

(612 citation statements)

References 224 publications

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“…[221][222][223] These channels mediate most of the fast excitatory transmission in the central nervous system and are thus involved in all brain functions. Their excessive activation plays a large role in epileptic phenomena, including the paroxysmal depolarization shift (the single-cell correlate of interictal spikes) and seizure discharges.…”

Section: Ionotropic Glutamate Receptorsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Ionotropic Glutamate Receptorsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…GluR agonists and antagonists are structurally similar to Glu, which allows them to bind onto the same receptors [242][243][244] . Activation of GluRs has been shown to mediate a large number of neuronal processes such as long-term potentiation and ischemic damage 245 .…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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“…AMPAR are heteromeric complexes composed of four subunits (GluR1, GluR2, GluR3, and GluR4), each of which has a binding pocket for the transmitter glutamate and can be expressed as flip or flop splice variant, which is regulated regionally (Black, 2005). Several distinct classes of AMPAR modulators have been reported (Kew and Kemp, 2005) such as aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone compound); benzamide compoundsF'ampakines' (CX516, CX546, and CX614); benzothiadiazides and related IDRA and PEPA compounds, and group of biarypropylsulfonamides (LY392098, LY404187, LY395153, LY503430). Positive AMPAR modulators do not bind to the glutamate binding site, but they interact with the receptor at an allosteric site and augment function by decreasing desensitization and/or deactivation.…”

Section: Introductionmentioning

confidence: 99%

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

Lipina

Weiss

Roder

2006

Neuropsychopharmacol

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In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5 + / + littermates, mGluR5 À/À mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5 À/À mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptorsFMK-801. PPI deficit of mGluR5 À/À mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia. Neuropsychopharmacology (2007) 32, 745-756.

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Ionotropic and metabotropic glutamate receptor structure and pharmacology

Cited by 687 publications

References 224 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

A Review of Glutamate Receptors I: Current Understanding of Their Biology

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

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