Elsevier

Progress in Neurobiology

Volume 54, Issue 5, 5 March 1998, Pages 581-618
Progress in Neurobiology

Glutamate receptors in the mammalian central nervous system

https://doi.org/10.1016/S0301-0082(97)00085-3Get rights and content

Abstract

Glutamate receptors (GluRs) mediate most of the excitatory neurotransmission in the mammalian central nervous system (CNS). In addition, they are involved in plastic changes in synaptic transmission as well as excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. The GluRs are divided into two distinct groups, ionotropic and metabotropic receptors. The ionotropic receptors (iGluRs) are further subdivided into three groups: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptor channels. The metabotropic receptors (mGluRs) are coupled to GTP-binding proteins (G-proteins), and regulate the production of intracellular messengers. The application of molecular cloning technology has greatly advanced our understanding of the GluR system. To date, at least 14 cDNAs of subunit proteins constituting iGluRs and 8 cDNAs of proteins coznstituting mGluRs have been cloned in the mammalian CNS, and the molecular structure, distribution and developmental change in the CNS, functional and pharmacological properties of each receptor subunit have been elucidated. Furthermore, the obtained clones have provided valuable tools for conducting studies to clarify the physiological and pathophysiological significances of each subunit. For example, the generation of gene knockout mice has disclosed critical roles of some GluR subunits in brain functions. In this article, we review recent progress in the research for GluRs with special emphasis on the molecular diversity of the GluR system and its implications for physiology and pathology of the CNS.

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.

Section snippets

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.

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