Glutamate receptors in the mammalian central nervous system
Introduction
Glutamate receptors (GluRs) mediate most of the excitatory neurotransmission in the mammalian central nervous system (CNS). They also participate in plastic changes in the efficacy of synaptic transmission underlying memory and learning, and the formation of neural networks during development (see Mayer and Westbrook, 1987b; Dingledine et al., 1988; Monaghan et al., 1989for reviews). Ironically, glutamate and related excitatory amino acids are toxic to central neurons. Excessive activation of GluRs during stress to the brain, such as ischemia, head trauma and epileptic seizures leads to the death of central neurons. The glutamate neurotoxicity may also be involved in the geneses of various neurodegenerative diseases (see Rothman and Olney, 1987; Choi, 1988; Choi and Rothman, 1990; Meldrum and Garthwaite, 1990for reviews). Thus, the GluRs are intimately involved in both the physiology and pathology of brain functions.
The GluRs are categorized into two distinct classes, ionotropic and metabotropic receptors (see Nakanishi, 1992; Seeburg, 1993; Hollmann and Heinemann, 1994for reviews). The ionotropic receptors (iGluRs) contain cation-specific ion channels, and are further subdivided into three groups:α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate(AMPA), kainate and N-methyl-D-aspartate (NMDA) receptor channels. On the other hand, the metabotropic receptors (mGluRs) are coupled to GTP-binding proteins (G-proteins) and modulate the production of intracellular messengers.
The application of molecular cloning technology has caused dramatic changes in the study of the GluR system. The first iGluR was cloned in 1989 with the expression-cloning approach (Hollmann et al., 1989). The cloning of the first mGluR was also accomplished using the same technique in 1991 (Houamed et al., 1991; Masu et al., 1991). To date, at least 14 cDNAs of iGluRs and 8 cDNAs of mGluRs have been identified in the mammalian CNS. In recent years, both physiology and pathology of GluR systems have been investigated extensively by using various techniques that manipulate expressions of GluR genes. The aim of this review is to summarize recent findings on GluRs, putting emphasis on describing the physiological and pathological significances of the molecular diversity of GluRs. We will first describe recent findings on iGluRs in terms of their molecular diversity, distribution in the CNS, ion channel properties, pharmacology, and physiological as well as pathophysiological significances. Then, we will describe the molecular diversity, physiology and pathophysiology of mGluRs.
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Classification
Traditionally, iGluRs have been divided into three major subtypes, AMPA, kainate and NMDA receptors, on the basis of agonist specificities. However, since neither agonist nor antagonist clearly distinguished between AMPA and kainate receptors, they were often collectively referred to as non-NMDA receptors. Cloning studies have demonstrated that they are distinct receptor complexes although they can be activated by the same agonists, notably AMPA receptors are activated by kainate and kainate
Metabotropic receptors
Glutamate activates not only iGluRs, but also mGluRs coupled to G-proteins (see Schoepp and Conn, 1993; Nakanishi, 1994; Pin and Duvoisin, 1995for reviews). It was first reported that glutamate activates inositol phosphate metabolism directly in striatal (Sladezek et al., 1985) and cerebellar granule cell cultures (Nicoletti et al., 1986b, Nicoletti et al., 1988) as well as in hippocampal slices (Nicoletti et al., 1986a). Thereafter, Sugiyama et al. (1987)have demonstrated that Xenopus oocytes
Concluding remarks
During the last decade, our understanding of the GluRs in the mammalian CNS has been advanced enormously by the application of molecular cloning technology. This technology has revealed that the molecular diversity of the GluRs is much larger than expected from the previous electrophysiological and pharmacological studies. To date, at least 14 iGluR subunits and 8 mGluR subtypes have been identified, and their molecular structure, distribution in the CNS together with developmental changes,
Acknowledgements
We are most grateful to Professor John W. Phillis of Wayne State University for his continuing encouragement in finishing this review. We would also like to thank the Human Frontier Science Program and the Ministry of Education, Science, Sports and Culture of Japan for support.
References (406)
- et al.
Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction
J. Biol. Chem.
(1992) - et al.
Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice
Cell
(1994) - et al.
Prolonged presence of glutamate during excitatory synaptic transmission to cerebellar Purkinje cells
Neuron
(1994) - et al.
Novel synaptic potentials in cerebellar Purkinje cells: probable mediation by metabotropic glutamate receptors
Neuropharmacology
(1993) - et al.
Pharmacological characterization of synaptic transmission through mGluRs in rat cerebellar slices
Neuropharmacology
(1997) - et al.
Synaptic plasticity: LTP and LTD
Curr. Opin. Neurobiol.
(1994) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy
Neuroscience
(1985)- et al.
Brief seizure episodes induce long-term potentiation and mossy fibre sprouting in the hippocampus
Trends Neurosci.
(1990) - et al.
Co-activation of metabotropic glutamate and N-methyl-D-aspartate receptors is involved in mechanisms of long-term potentiation maintenance in rat hippocampal CA1 neurons
Neuroscience
(1993) - et al.
Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop
Neuron
(1995)
Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development
Neuron
Cloning of a putative glutamate receptor: a low affinity kainate-binding subunit
Neuron
Review: Neurotransmitter receptors II
AMPA and kainate receptors. Neuropharmacology
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid attenuates N-methyl-D-aspartate-induced neuronal cell death in cortical cultures via a reduction in delayed Ca2+ accumulation
Neuropharmacology
Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel
Neuron
Activation of glutamate metabotropic receptors induces long-term potentiation
Eur. J. Pharmacol.
On the mechanism of long-term potentiation induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) in rat hippocampal slices
Neuropharmacology
Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block
Neuron
Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death
Eur. J. Pharmacol.
Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit
Neuron
The anticonvulsive effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice
Epilepsy Res.
Activation of metabotropic receptors has a neuroprotective effects in a rodent model of focal ischaemia
Eur. J. Pharmacol.
Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage
Trends. Neurosci.
D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia
Neuropharmacology
The distribution of glutamate receptors in cultured rat hippocampal neurons: postsynaptic clustering of AMPA-selective subunits
Neuron
Evidence for involvement of N-methylaspartate receptors in “wind-up” of class 2 neurones in the dorsal horn of the rat
Brain Res.
1-BCP, a memory-enhancing agent, selectively potentiates AMPA-induced [3H]norepinephrine release in rat hippocampal slices
Neuropharmacology
A cure for wind up: NMDA receptor antagonists as potential analgesics
Trends Pharmacol. Sci.
Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation
Neuropharmacology
GYKI 52466, a 2,3-benzodiazepine, is a highly selective, non-competitive antagonist of AMPA/kainate receptor responses
Neuron
Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenyl-glycine and (RS)-α-methyl-4-carboxyphenylglycine
Eur. J. Pharmacol.
Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death
Neuron
Effects of a spider toxin on the glutaminergic synapse of lobster muscle
J. Physiol. (Lond.)
The primary afferent depolarizing action of kainate in the rat
Br. J. Pharmacol.
Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice
Cell
Transfection of N-methyl-D-aspartate receptors in a nonneuronal cell line leads to cell death
J. Neurochem.
Chemical structure of joro spider toxin (JSTX)
Biomed. Res.
N-methyl-D-aspartate-activated channels of mouse central neurons in magnesium-free solutions
J. Physiol. (Lond.)
Quisqualate- and kainate-activated channels in mouse central neurones in culture
J. Physiol. (Lond.)
The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture
J. Physiol. (Lond.)
Activity-dependent regulation of N-methyl-D-aspartate receptor subunit expression in rat cerebellar granule cells
Eur. J. Neurosci.
Kainate receptor gene expression in the developing rat brain
J. Neurosci.
Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors
Nature (Lond.)
Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus
J. Physiol. (Lond.)
Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway
Nature (Lond.)
Transsynaptic neuronal loss induced in hippocampal slice cultures by a herpes simplex virus vector expressing the GluR6 subunit of the kainate receptor
Proc. natn. Acad. Sci. U. S. A.
Excitatory synaptic potentials dependent on metabotropic glutamate receptor activation in guinea-pig hippocampal pyramidal cells
J. Physiol. (Lond.)
A single amino acid determines the subunit-specific spider toxin block of α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor channels
Proc. natn. Acad. Sci. U. S. A.
A synaptic model of memory: long-term potentiation in the hippocampus
Nature (Lond.)
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