GABA and GABA Receptors in the Central Nervous System and Other Organs

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γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.

Introduction

Approximately 30 years have passed since γ-aminobutyrate (GABA), which is a well-known amino acid present in bacteria and plants, was first recognized as an inhibitory neurotransmitter in the mammalian brain. To date, dozens of molecules, including monoamine, acetylcholine, amino acids, and peptides, have been classified as neurotransmitters. In the 1970s, neurotransmission was thought to be controlled by two major systems: the monoaminergic system and the cholinergic system. In addition to these systems, amino acids such as GABA and glycine have also received attention. It was in the latter half of the 1970s that many neuropeptides were recognized to be involved in neurotransmission, and much attention was given to these neuropeptides. During that period, interest in amino acids diminished. GABA has recently regained attention because of the dramatic progress in brain research that has revealed the diversity of GABA receptors and their physiological functions. The functions of GABA receptors in the endocrine system (Racagni and Donoso, 1986), various central nervous system (CNS) diseases (Tanaka and Bowery, 1996), and peripheral tissues and organs are being studied and should clarify the physiological functions of GABA. The importance of GABA research is reflected in the number of scientific publications related to this molecule. AMEDLINE search of papers with the keyword GABA yielded approximately 1000 references per year from 1980 to 1985, 400 references per year from 1986 to 1990, and more than 1600 references per year from 1991 to 1999. During 2000, approximately 150 references related to GABA were added per month. It has been hypothesized that GABA is a multifunctional molecule that has different functions in the nervous system that are situation dependent. GABA influences neural migration (Behar et al., 1994, Behar et al., 1996), acts as a neurotrophic factor (Barbin et al., 1993, Obata, 1997), and facilitates neurite extension (Behar et al., 1998).

In this review, we first discuss how GABA is synthesized in the brain, with emphasis on the metabolic interrelation of GABAergic and glutamatergic neurons and glial cells, on the rate-limiting enzyme glutamate decarboxylase (GAD), and on polyamines in alternative GABA synthesis pathways. This is followed by a description of GABAA receptors and a brief description of GABAB receptors. Finally, we discuss the possible roles of the GABA system in brain development and peripheral tissues. This review will not address the pharmacological aspects of the GABA system because this has been covered elsewhere (Macdonald and Olsen, 1994, Sieghart, 1995, Kerr and Ong, 1995, Mehta and Ticku, 1999). We have also omitted discussion of the spinal cord for the same reason (Malcangio and Bowery, 1996).

Section snippets

Discovery of GABA and Its Precursor in the Brain of Vertebrates

GABA was first identified in mammalian brain by Awapara et al. (1950) and by Roberts and Frankel (1950). In their reports, Awapara et al. suggested that a novel enzyme was responsible for catalyzing the conversion of glutamate to GABA. When brain homogenates of rat and rabbit were incubated with glutamate, the decrease in glutamate levels paralleled the increase in GABA levels. Roberts and Frankel and Udenfriend (1950) then demonstrated that glutamate is a precursor of GABA. In 1951, very high

GABA Receptors

GABA can interact with three types of receptors: GABAA, GABAB, and GABAC. The GABAA and GABAC receptors are members of the ligand-gated Cl channel superfamily and mediate the fast inhibitory activity of GABA (Macdonald and Olsen, 1994, Rabow et al., 1995, Sieghart, 1995). GABAB receptors belong to the large family of GTP-binding protein-coupled receptors and regulate the K+ and Ca2 + channels that mediate the long-term inhibitory actions of GABA (Kerr and Ong, 1995).

GABA System and Development of Brain

GABA is one of the first neurotransmitters detected during development of the CNS and is thought to play a role in neural development.

Tissue Distribution of GABA and GAD

GABA, GAD, and GABA-T have been found in a variety of tissues outside the brain and spinal cord. Quantitative and semiquantitative data for GABA, GAD, and GABA-T levels in peripheral tissues in mammals have been summarized by Tanaka (1985) and Erdö and Kiss (1986). The tissues include blood, blood vessels, spleen, heart, skeletal muscle, gastrointestinal tract, liver, pancreas, kidney, urinary bladder, male and female reproductive organs, lung, pituitary, thyroid, adrenal gland, thymus,

Concluding Remarks

It is thought that GABA exerts its inhibitory effect via acting GABAA receptors in adult mammalian brain. However, the effect is not uniform, and it is complicated by heterogeneity of the subunit composition of receptors, by modulation of various intrinsic and extrinsic chemical substances, and by subunit phosphorylation. Moreover, the diversity of neurons must be considered. Pharmacological research on GABAA receptor heterogeneity, which was not addressed in this review, has made it possible

Acknowledgments

The invaluable contributions of Drs. H. Hayashi (Biochemistry Department), R. Yoshida (2nd Physiology Department), and Fangyu Wang (Anatomy Department) of Osaka Medical College and Carlos E. de Carvalho (Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases, Osaka University) to this review are gratefully acknowledged. In addition, we thank T. Kanayama and T. Miyahara for their secretarial help.

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