Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging

doi:10.1016/S0301-0082(97)00055-5

Progress in Neurobiology

Volume 54, Issue 4, 2 March 1998, Pages 369-415

https://doi.org/10.1016/S0301-0082(97)00055-5 Get rights and content

Abstract

Forty years of research into the function of l-glutamic acid as a neurotransmitter in the vertebrate central nervous system (CNS) have uncovered a tremendous complexity in the actions of this excitatory neurotransmitter and an equally great complexity in the molecular structures of the receptors activated by l-glutamate. l-Glutamate is the most widespread excitatory transmitter system in the vertebrate CNS and in addition to its actions as a synaptic transmitter it produces long-lasting changes in neuronal excitability, synaptic structure and function, neuronal migration during development, and neuronal viability. These effects are produced through the activation of two general classes of receptors, those that form ion channels or “ionotropic” and those that are linked to G-proteins or “metabotropic”. The pharmacological and physiological characterization of these various forms over the past two decades has led to the definition of three forms of ionotropic receptors, the kainate (KA), AMPA, and NMDA receptors, and three groups of metabotropic receptors. Twenty-seven genes are now identified for specific subunits of these receptors and another five proteins are likely to function as receptor subunits or receptor associated proteins. The regulation of expression of these protein subunits, their localization in neuronal and glial membranes, and their role in determining the physiological properties of glutamate receptors is a fertile field of current investigations into the cell and molecular biology of these receptors. Both ionotropic and metabotropic receptors are linked to multiple intracellular messengers, such as Ca²⁺, cyclic AMP, reactive oxygen species, and initiate multiple signaling cascades that determine neuronal growth, differentiation and survival. These cascades of complex molecular events are presented in this review.

Section snippets

Glutamate receptors: their role in the function of neurons of the central nervous system

Approximately 40 years have elapsed since the first demonstration that a direct injection of monosodium glutamate into the brain induces seizures (Hayashi, 1954) and its application on the cerebral cortex causes massive depolarization and spreading depression (Van Harreveld, 1959). These early observations of a potential role for glutamate as an excitatory agent in the central nervous system (CNS), particularly one involved in the generation of abnormal electrical activity associated with

Glutamate receptor classification

The pharmacological and physiological properties of neuronal glutamate receptors have been reviewed extensively (Nistri and Constanti, 1979; Watkins and Evans, 1981; McLennan, 1983; Watkins and Olverman, 1987; Shinozaki, 1988; Watkins et al., 1990; Krogsgaard-Larsen et al., 1991; Watkins, 1991; Wong and Kemp, 1991). An evolution in the concepts of the distinct pharmacological and physiological properties of different glutamate receptors in CNS neurons has led to the classification scheme shown

Glutamate receptor cDNAs and molecular classification of the receptors

The diversity of physiological responses and pharmacological classifications of the EAA receptors has now been matched to a considerable degree with a great complexity in the structure of the receptor complexes. The molecular structures of these receptors have been obtained through successful cloning of the complementary DNAs (cDNAs). Even though only seven years has elapsed since the first cloning and expression of a functional AMPA/KA receptor, great progress has been made in terms of a

Phosphorylation of ionotropic receptors

An important aspect of all ionotropic receptors is their dependence on intracellular ATP for full activity. This has been traced to the apparent phosphorylation of the receptor proteins and the consequent modulation of receptor responses. For example, the amplitude of channel current of KA receptors is strongly enhanced by phosphorylation of GluR6 by cyclic AMP-dependent protein kinase (PKA) (Raymond et al., 1993; Wang et al., 1993) and that of both KA and AMPA receptors by phosphorylation by

AMPA, KA, NMDA and mGluR receptor expression, trafficking, and membrane localization

Since the first successful cloning of the cDNA for GluR1, the molecular biology of AMPA and KA receptors quickly outstripped our understanding of the cell biology and physiology of these receptors. One of the most puzzling issues is the presence of multiple forms of receptors within the same cells and even within the same subsynaptic region. The results of the studies described in the preceding sections confirm the presence of both AMPA and KA receptors in the same cells of the CNS. From a cell

Glutamate-induced necrosis and apoptosis

As was mentioned in an earlier section, the phenomenon of excitotoxicity, i.e. cell necrosis that results from excessive glutamate activation of its surface receptors, has been linked to several pathologic states in the nervous system such as seizures, ischemia, anoxia, hypoglycemia, and inflammation associated with viral infections (Simon et al., 1984; Meldrum, 1985; Schwarcz and Meldrum, 1985; Garthwaite et al., 1986; Choi, 1987, Choi, 1988, Choi, 1990, Choi, 1992; Maragos et al., 1987; Cox

Intracellular signaling by ROS: the role of G proteins, kinases and phosphatases

The formation of ROS and reactive nitrogen species (RNS), such as $.$ NO and NO⁺, has been usually considered a sign of oxidative stress that puts cells on the course to apoptotic death. However, within the last few years, it has become abundantly clear that these reactive species are another form of intracellular signaling and that transient increases in the levels of ROS and RNS may activate familiar pathways of signal transduction, such as phosphorylation and dephosphorylation of proteins,

Glutamate-induced oxidative stress in neurodegeneration associated with aging

Aging at the cellular and molecular level remains a very difficult process to define. The initiating events for macromolecular changes such as DNA breakdown, protein structural and functional alterations, and membrane structural defects are not known. One hypothesis suggests that the molecular abnormalities that appear in a cell undergoing the aging process are pre-programmed, therefore cell viability is limited by the genetic and protein synthetic program that a cell inherits. An alternative

Conclusions

The discovery of the multiple roles played by the neurotransmitter glutamate in synaptic transmission—brain development, acquisition and storage of new information in the brain, and the initiation of neurotoxic events—has been one of the most remarkable achievements in the neurosciences over the past two decades. The different microenvironments in neurons in which these receptors operate may determine the intracellular signals generated by activation of the ion channels, the effects of the

Acknowledgements

The author thanks Dr M. Michaelis for valuable comments on this manuscript and Ms Nancy Harmony for expert editorial work. The author's work was supported by grants AG12993 from the National Institute on Aging and AA04732 and 11419 from the National Institute of Alcoholism and Alcohol Abuse. The support of the Center for Neurobiology and Immunology Research is also acknowledged.

References (590)

T. Abe et al.
Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca²⁺ signal transduction
J. Biol. Chem.
(1992)
A. Abeliovich et al.
Modified hippocampal long-term potentiation in PKCγ-mutant mice
Cell
(1993)
G. Adam et al.
Role of actin in the organisation of brain postsynaptic densities
Brain Res. Molec. Brain Res.
(1996)
G.L. Aistrup et al.
Ion channel properties of a protein complex with characteristics of a glutamate/N-methyl-d-aspartate receptor
FEBS Lett.
(1996)
E. Aizenman et al.
Selective modulation of NMDA responses by reduction and oxidation
Neuron
(1989)
N. Akaike et al.
Spider toxin blocks excitatory amino acid responses in isolated hippocampal pyramidal neurons
Neurosci. Lett.
(1987)
V. Anantharam et al.
Combinatorial RNA splicing alters the surface charge on the NMDA receptor
FEBS Lett.
(1992)
M. Ankarcrona et al.
Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function
Neuron
(1995)
J. Avruch et al.
Raf meets Ras: completing the framework of a signal transduction pathway
TIBS
(1994)
K.K. Babcock et al.
A synaptic membrane glycine-, glutamate- and thienylcyclohexylpiperidine-binding protein: isolation and immunochemical characterization
Neurochem. Int.
(1996)

R. Balázs et al.

N-Methyl-d-aspartate promotes the survival of cerebellar granule cells in culture

Neuroscience

(1988)

J.M. Barnes et al.

Molecular characteristics of excitatory amino acid receptors

Prog. Neurobiol.

(1992)

A. Baskys et al.

NMDA and quisqualate reduce a calcium-dependent potassium current by a protein kinase-mediated mechanism

Neurosci. Lett.

(1990)

M.G. Battelli et al.

Excitotoxic increase of xanthine dehydrogenase and xanthine oxidase in the rate olfactory cortex

Develop. Brain Res.

(1995)

A. Baude et al.

The metabotropic glutamate receptor (mGluR1a) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction

Neuron

(1993)

E.J. Beilharz et al.

Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rate: evidence for apoptosis during selective neuronal loss

Molec. Brain Res.

(1995)

J.A. Bennett et al.

Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop

Neuron

(1995)

M. Benveniste et al.

Kinetic analysis of antagonist action at N-methyl-d-aspartic acid receptors. Two binding sites each for glutamate and glycine

Biophys. J.

(1991)

B. Bettler et al.

Review: Neurotransmitter receptors II: AMPA and kainate receptors

Neuropharmacol.

(1995)

B. Bettler et al.

Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development

Neuron

(1990)

B. Bettler et al.

Cloning of a putative glutamate receptor: a low affinity kainate-binding subunit

Neuron

(1992)

P.J. Birch et al.

6,7-Dinitro-quinoxaline-2,3-dion and 6-nitro,7-cyano-quinoxaline-2,3-dion antagonist responses to NMDA in the rat spinal cord via an action at the strychnine-insensitive glycine receptor

Eur. J. Pharmacol.

(1988)

P. Bochet et al.

Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel

Neuron

(1994)

L.H. Boise et al.

bcl-x, a bcl-2-Related gene that functions as a dominant regulator of apoptotic cell death

Cell

(1993)

D.S. Bredt et al.

Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase

Neuron

(1991)

D.S. Bredt et al.

Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites

J. Biol. Chem.

(1992)

G.J. Brewer et al.

NMDA receptor regulation of neuronal morphology in cultured hippocampal neurons

Neurosci. Lett.

(1989)

N. Brose et al.

Protein chemical characterization and immunocytochemical localization of the NMDA receptor subunit NMDA R1

J. Biol. Chem.

(1993)

N. Brose et al.

Differential assembly of coexpressed glutamate receptor subunits in neurons of rat cerebral cortex

J. Biol. Chem.

(1994)

A.M. Buchan et al.

Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats

Neurosci. Lett.

(1991)

V. Budnik et al.

Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg

Neuron

(1996)

R.D. Burgoyne et al.

N-Methyl-d-aspartate raises cytosolic calcium concentration in rat cerebellar granule cells in culture

Neurosci. Lett.

(1988)

N. Burnashev et al.

Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit

Neuron

(1992)

S.P. Butcher et al.

Extracellular purine catabolite and amino acid levels in the rat striatum during severe hypoglycemia: effects of 2-amino-5-phosphonovalerate

Neurochem. Int.

(1987)

M. Buttini et al.

Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat

Neurosci.

(1996)

N.G. Carlson et al.

Identification of amino acids in the glutamate receptor, GluR3, important for antibody-binding and receptor-specific activation

J. Biol. Chem.

(1997)

L. Castro et al.

Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide

J. Biol. Chem.

(1994)

P.L. Chazot et al.

Molecular characterization of N-methyl-d-aspartate receptors expressed in mammalian cells yields evidence for the coexistence of three subunit types within a discrete receptor molecule

J. Biol. Chem.

(1994)

K.O. Cho et al.

The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein

Neuron

(1992)

D.W. Choi

Glutamate neurotoxicity and diseases of the nervous system

Neuron

(1988)

J.A. Corbett et al.

Interleukin-1b-induced formation of EPR-detectable iron–nitrosyl complexes in islets of langerhans

J. Biol. Chem.

(1991)

C.W. Cotman et al.

Anatomical organization of excitatory amino acid receptors and their pathways

TINS

(1987)

J.A. Cox et al.

Excitatory amino acid neurotoxicity at the N-methyl-d-aspartate receptor in cultured neurons: role of the voltage-dependent magnesium block

Brain Res.

(1989)

P. Agostinho et al.

Impairment of excitatory amino acid transporter activity by oxidative stress conditions in retinal cells: effect of antioxidants

FASEB J.

(1997)

E. Aizenman et al.

Oxygen free radicals regulate NMDA receptor function via a redox modulatory site

Neuron

(1980)

H. Altmann et al.

Effects of glutamate, aspartate and two presumed antagonists on feline rubrospinal neurones

Pflugers Arch. Gen. Physiol.

(1976)

P. Andersen et al.

The excitation of thalamic neurons by acetylcholine

Acta Physiol. Scand.

(1964)

C. Aoki et al.

Cellular and subcellular localization of NDAM-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats

J. Neurosci.

(1994)

A. Artola et al.

Long-term potentiation and NMDA receptors in rat visual cortex

Nature

(1987)

A. Atlante et al.

Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation

J. Neurochem.

(1997)

Cited by (489)

Abdominal Pain
2022, Comprehensive Pharmacology
Visceral pain describes pain originating from the internal organs and is often variable in its experience, poorly localized and difficult to treat. Despite its prevalence, chronic visceral pain is clinically challenging to delineate its etiology based on symptoms. Although conventional analgesics offer relief for acute visceral pain, prolonged use is associated with tolerance, unwanted side effects and hyperalgesia. Chronic visceral pain is characterized by hypersensitivity to stimuli such as inflammation or mechanical distension may arise due to a peripheral augmentation of primary afferent signals, or may be due to central facilitation at spinal and supraspinal levels affecting descending nociceptive modulation. Abdominal pain as a central defining feature of common pathological conditions; in this review we focus in abdominal pain originating from the colon and the bladder, as observed in patients with irritable bowel syndrome, inflammatory bowel disease, and painful bladder syndrome. We discuss the neural innervation of the colon and bladder with attention to the nerves involved in visceral nociception. We discuss the etiology of chronic visceral hypersensitivity and the use of animal model in the identification of mediators and novel molecular mechanisms that may serve as novel targets in the development of better pharmacological approaches to treat chronic abdominal pain.
Membrane transport | Ligand-operated membrane channels: Calcium (Glutamate)
2021, Encyclopedia of Biological Chemistry: Third Edition
Mammalian central nervous system neurons are characterized by differential responses to incoming stimuli and storage of the information elicited by external stimuli. Calcium (Ca²⁺) influx through select populations of neurotransmitter-activated receptors, the glutamate receptors, when coupled with the induction of Ca²⁺ release from intracellular stores, initiates key molecular interactions and enzyme activities that lead to long-term changes in transcription, protein synthesis, and neuronal responses to external stimuli. Glutamate receptor ion channels fall into three main classes based on molecular structure and pharmacological sensitivities. These ligand-activated ion channels are differentially permeable to Ca²⁺ and their activation can lead to either long-term potentiation or depression of synaptic activity.
Mechanisms and repair strategies for white matter degeneration in CNS injury and diseases
2021, Biochimica et Biophysica Acta - Molecular Basis of Disease
White matter degeneration is an important pathophysiological event of the central nervous system that is collectively characterized by demyelination, oligodendrocyte loss, axonal degeneration and parenchymal changes that can result in sensory, motor, autonomic and cognitive impairments. White matter degeneration can occur due to a variety of causes including trauma, neurotoxic exposure, insufficient blood flow, neuroinflammation, and developmental and inherited neuropathies. Regardless of the etiology, the degeneration processes share similar pathologic features. In recent years, a plethora of cellular and molecular mechanisms have been identified for axon and oligodendrocyte degeneration including oxidative damage, calcium overload, neuroinflammatory events, activation of proteases, depletion of adenosine triphosphate and energy supply. Extensive efforts have been also made to develop neuroprotective and neuroregenerative approaches for white matter repair. However, less progress has been achieved in this area mainly due to the complexity and multifactorial nature of the degeneration processes. Here, we will provide a timely review on the current understanding of the cellular and molecular mechanisms of white matter degeneration and will also discuss recent pharmacological and cellular therapeutic approaches for white matter protection as well as axonal regeneration, oligodendrogenesis and remyelination.
Metabotropic Glutamate Receptors at the Aged Mossy Fiber – CA3 Synapse of the Hippocampus
2021, Neuroscience
Metabotropic glutamate receptors (mGluRs) are a group of G-protein-coupled receptors that exert a broad array of modulatory actions at excitatory synapses of the central nervous system. In the hippocampus, the selective activation of the different mGluRs modulates the intrinsic excitability, the strength of synaptic transmission, and induces multiple forms of long-term plasticity. Despite the relevance of mGluRs in the normal function of the hippocampus, we know very little about the changes that mGluRs functionality undergoes during the non-pathological aging. Here, we review data concerning the physiological actions of mGluRs, with particular emphasis on hippocampal area CA3. Later, we examine changes in the expression and functionality of mGluRs during the aging process. We complement this review with original data showing an array of electrophysiological modifications observed in the synaptic transmission and intrinsic excitability of aged CA3 pyramidal cells in response to the pharmacological stimulation of the different mGluRs.
Gyroxin, a toxin from Crotalus durissus terrificus snake venom, induces a calcium dependent increase in glutamate release in mice brain cortical synaptosomes
2020, Neuropeptides
Gyroxin is a thrombin-like toxin obtained from the venom of the South American rattlesnake, Crotalus durissus terrificus. Literature has reported “gyroxin syndrome” characterized, in mice, as series of aberrant motor behavior, known as barrel rotation, mainly after intraperitoneal administration. Despites several studies, a physiological mechanism of “gyroxin syndrome” are still not completely understood. In this context, alterations on the central nervous system (CNS), especially causing neurotoxic events, are pointed out as likely candidates. Then, we decided to investigate whether gyroxin induces alterations in glutamate release, one of the most important neurotransmitter involved in neurotoxicity. For that, we performed all experiments, in vitro, using a model of mice brain cortical synaptosomes. Notably, our results indicate that the administration of gyroxin on purified presynaptic brain cortical terminals resulted in an extracellular Ca²⁺- dependent raise in glutamate release. Indeed, our results also showed that gyroxin increases intrasynaptosomal calcium (Ca²⁺) levels through acting on voltage gated calcium channels (VGCC), specifically N and P/Q subtypes. Moreover, our data show that gyroxin increases exocytosis rate. Interestingly, these data suggest that gyroxin might induce neurotoxicity by increasing glutamate levels. However, future investigations are needed in order to elucidate the nature of the following events.
4,4′-Dichlorodiphenyl diselenide reverses a depressive-like phenotype, modulates prefrontal cortical oxidative stress and dysregulated glutamatergic neurotransmission induced by subchronic dexamethasone exposure to mice
2019, Journal of Psychiatric Research
Dexamethasone (DEX) is a synthetic agonist of glucocorticoid receptors that has been associated with neurotoxicity and neuropsychiatric diseases. (p-ClPhSe)₂ is an organoselenium compound reported to have antioxidant, antidepressant-like, and neuroprotective actions. This study investigated whether antioxidant activity and modulation of the glutamatergic system contribute to the antidepressant-like effect of (p-ClPhSe)₂ in mice subchronically exposed to DEX. Swiss mice received intraperitoneal injections of DEX (2 mg/kg) or saline (vehicle) once a day for 21 days. After, the mice received (p-ClPhSe)₂ (1–10 mg/kg) or mineral oil (vehicle) by the intragastric route (i.g.) for 7 days. The mice exposed to DEX were treated with fluoxetine (20 mg/kg, i.g.) once a day for 7 days. 24 h after the last treatment, the animals performed the locomotor activity (LMA), tail suspension, and forced swimming tests. Ex vivo assays were performed in samples of prefrontal cortex (PFC). The results show that (p-ClPhSe)₂ reversed depressive-like behavioral phenotype induced by DEX without affecting LMA. Further, (p-ClPhSe)₂ at all doses reduced ROS levels and increased CAT activity in the PFC of DEX-exposed mice. The highest dose of (p-ClPhSe)₂ was effective against the decrease of SOD activity in the PFC of mice exposed to DEX. (p-ClPhSe)₂ increased the [³H] glutamate uptake/release and decreased the Na⁺/K⁺-ATPase activity as well as the EAAT1 and NMDA R2A protein contents in the PFC of DEX-exposed mice. Regarding the NMDA R2B levels, there was no difference among experimental groups. In conclusion, this study reveals the effectiveness of (p-ClPhSe)₂ in reversing the depressive-like phenotype of DEX-exposed mice. In addition, (p-ClPhSe)₂ modulated oxidative stress and glutamate neurotransmission in the PFC of mice subchronically exposed to DEX.

View all citing articles on Scopus

View full text

Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging

Abstract

Section snippets

Glutamate receptors: their role in the function of neurons of the central nervous system

Glutamate receptor classification

Glutamate receptor cDNAs and molecular classification of the receptors

Phosphorylation of ionotropic receptors

AMPA, KA, NMDA and mGluR receptor expression, trafficking, and membrane localization

Glutamate-induced necrosis and apoptosis

Intracellular signaling by ROS: the role of G proteins, kinases and phosphatases

Glutamate-induced oxidative stress in neurodegeneration associated with aging

Conclusions

Acknowledgements

J. Biol. Chem.

Cell

Brain Res. Molec. Brain Res.

FEBS Lett.

Neuron

Neurosci. Lett.

FEBS Lett.

Neuron

TIBS

Neurochem. Int.

Neuroscience

Prog. Neurobiol.

Neurosci. Lett.

Develop. Brain Res.

Neuron

Molec. Brain Res.

Neuron

Biophys. J.

Neuropharmacol.

Neuron

Neuron

Eur. J. Pharmacol.

Neuron

Cell

Neuron

J. Biol. Chem.

Neurosci. Lett.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

Neuron

Neurosci. Lett.

Neuron

Neurochem. Int.

Neurosci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuron

J. Biol. Chem.

TINS

Brain Res.

Impairment of excitatory amino acid transporter activity by oxidative stress conditions in retinal cells: effect of antioxidants

FASEB J.

Oxygen free radicals regulate NMDA receptor function via a redox modulatory site

Neuron

Effects of glutamate, aspartate and two presumed antagonists on feline rubrospinal neurones

Pflugers Arch. Gen. Physiol.

The excitation of thalamic neurons by acetylcholine

Acta Physiol. Scand.

Cellular and subcellular localization of NDAM-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats

J. Neurosci.

Long-term potentiation and NMDA receptors in rat visual cortex

Nature

Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation

J. Neurochem.