Glutamate receptor ion channels.

The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

/pdf/glutamate-receptor-ion-channels-structure-regulation-and-148yts0p6h.pdf

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Dennis W. ChoiDepartment of Neurology, Stanford University, Stanford,California 94305Steven M. RothmanDepartments of Pediatrics, Neurology, and Anatomy and Neurobiology,Washington University, St. Louis, Missouri 63110The human brain depends on its blood supply for a continuous supply ofoxygen and glucose. Irreversible brain damage occurs if blood flow isreduced below about 10 ml/100 g tissue/min and if blood flow is completelyinterrupted, damage will occur in only a few minutes. Unfortunately, suchreductions (ischemia) are common in disease states: either localized individual vascular territories, as in stroke; or globally, as in cardiac arrest.Cerebral hypoxia can also occur in isolation, for example in respiratoryarrest, carbon monoxide poisoning, or near-drowning; pure glucose depri-vation can occur in insulin overdose or a variety of metabolic disorders.As a group, these disorders are a leading cause of neurological disabilityand death; stroke alone is the third most common cause of death in NorthAmerica.Despite its clinical importance, little is known about the cellular patho-genesis of hypoxic-ischemic brain damage, and at present there is noeffective therapy. A critical question has been why brain, more than mostother tissues, is so vulnerable to hypoxic-ischemic insults. In particular,certain neuronal subpopulations, such as hippocampal field CA1 andneocortical layers 3, 5, and 6, are characteristically destroyed after sub-maximal hypoxic-ischenfic exposure. A possible answer has emerged inthe last few years: At least some of this special vulnerability may beaccounted for by the central neurotoxicity of the endogenous excitatory1710147-006X/90/0301 ~:1171 $02.00www.annualreviews.org/aronline Annual Reviews

The role of glutamate neurotoxicity in hypoxic- ischemic neuronal death

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

/pdf/contribution-of-central-neuroplasticity-to-pathological-pain-m3ucvtce0k.pdf

Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Two novel subunits of the mouse NMDA receptor channel, the epsilon 2 and epsilon 3 subunits, have been identified by cloning and expression of complementary DNAs. The heteromeric epsilon 1/zeta 1, epsilon 2/zeta 1 and epsilon 3/zeta 1 NMDA receptor channels exhibit distinct functional properties in affinities for agonists and sensitivities to competitive antagonists and Mg2+ block. In contrast to the wide distribution of the epsilon 1 and zeta 1 subunit messenger RNAs in the brain, the epsilon 2 subunit mRNA is expressed only in the forebrain and the epsilon 3 subunit mRNA is found predominantly in the cerebellum. The epsilon 1/zeta 1 and epsilon 2/zeta 1 channels expressed in Xenopus oocytes, but not the epsilon 3/zeta 1 channel, are activated by treatment with 12-O-tetradecanoylphorbol 13-acetate. These findings suggest that the molecular diversity of the epsilon subunit family underlies the functional heterogeneity of the NMDA receptor channel.

Molecular diversity of the NMDA receptor channel

Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical slices 7-Cl KYNA (10-100 microM) noncompetitively inhibited N-Me-D-Asp responses, and this effect could be reversed by the addition of glycine (100 microM) or D-serine (100 microM). Radioligand binding experiments showed that 7-Cl KYNA had a much higher affinity for the strychnine-insensitive [3H]glycine binding site (IC50 = 0.56 microM) than for the N-Me-D-Asp (IC50 169 microM), quisqualate (IC50 = 153 microM), or kainate (IC50 greater than 1000 microM) recognition sites. In whole-cell patch-clamp recordings from rat cortical neurones in culture, the inhibitory effects of 7-Cl KYNA on N-Me-D-Asp-induced currents could not be overcome by increasing the N-Me-D-Asp concentration but could be reversed by increasing the glycine concentration. 7-Cl KYNA could completely abolish N-Me-D-Asp responses, including basal responses in the absence of added glycine, suggesting that it may possess negative modulatory effects at the glycine site. These findings indicate that the glycine modulatory site is functional in intact adult tissue and that 7-Cl KYNA should prove to be a selective tool for elucidating the involvement of this site in physiological and pathological events mediated by N-Me-D-Asp receptors.

https://www.pnas.org/content/pnas/85/17/6547.full.pdf

7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex.

7-Chlorokynurenate (7-Cl KYNA) and 3-amino-1-hydroxypyrrolid-2-one (HA-966), two selective antagonists of the glycine site on the N-methyl-D-aspartate (NMDA) receptor, have been used to assess the involvement of this site in the neurodegeneration resulting from injection of excitotoxins in the rat brain In the rat striatum, reductions in the enzymes choline acetyltransferase (CAT) and glutamate decarboxylase (GAD), occurring 7 days after a unilateral, intrastriatal injection of quinolinate (200 nmol), were prevented in a dose-dependent manner by intrastriatal administration of 7-Cl KYNA (10 - 50 nmol) and HA-966 (200 - 500 nmol) 1 h after the excitotoxin In the rat hippocampus, degeneration of pyramidal and granule neurons caused by direct injection of quinolinate (60 nmol) was completely prevented by 7-Cl KYNA (50 nmol) and partially by HA-966 (500 nmol) injected intrahippocampally 1 h after the excitotoxin In the rat striatum, 7-Cl KYNA (50 nmol) and HA-966 (500 nmol) also reduced neurotoxicity caused by intrastriatal injection of NMDA (200 nmol), but not that caused by the 'non-NMDA' receptor agonists DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate The time course of protective effects of 7-Cl KYNA and HA-966 in the striatum was similar to that previously observed with the uncompetitive NMDA receptor antagonist MK-801, indicating that activation of the glycine site contributes to the delayed degeneration of neurons which occurs over the first 5 h following quinolinate injection The neuroprotective effects of both 7-Cl KYNA and HA-966 in the rat striatum appear to be mediated via the glycine site on the NMDA receptor as they were completely reversed by D-serine, but not L-serine These results indicate that activation of the glycine site is essential for the expression of the delayed degeneration of neurons resulting from intracerebral injection of an NMDA receptor agonist, a process which bears similarities to the delayed neurodegeneration which results from a period of cerebral ischaemia

Protection Against N-methyl-D-aspartate Receptor-Mediated Neuronal Degeneration In Rat Brain by 7-chlorokynurenate and 3-amino-1-hydroxypyrrolid-2-one, Antagonists at The Allosteric Site for Glycine.

It is now firmly established that the widespread actions of the excitatory amino acid neurotransmitters glutamate and aspartate in the mammalian central nervous system (CNS) are mediated by distinct receptor sub-types. Amongst these, the N-methyl-D-aspartate (NMDA) receptor has been characterized most fully in terms of its pharmacological and biophysical properties (Watkins and Evans, 1981; Mayer and Westbrook, 1987). The NMDA receptor can be divided into three functional domains (Foster and Fagg, 1987): a transmitter recognition site, an ion channel and an allosteric site activated by glycine. This chapter will review the glycine site on the NMDA receptor, describe its pharmacology, including the identification of selective antagonists, and discuss experiments with these compounds which have attempted to determine the relevance of activation of the glycine site in vivo for neurodegenerative phenomena mediated by NMDA receptor activation.

The glycine site on the NMDA receptor: pharmacology and involvement in NMDA receptor-mediated neurodegeneration.

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7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex.

Protection Against N-methyl-D-aspartate Receptor-Mediated Neuronal Degeneration In Rat Brain by 7-chlorokynurenate and 3-amino-1-hydroxypyrrolid-2-one, Antagonists at The Allosteric Site for Glycine.

The glycine site on the NMDA receptor: pharmacology and involvement in NMDA receptor-mediated neurodegeneration.