International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update

Abstract

In this review we attempt to summarize experimental evidence on the existence of defined native GABA(A) receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA(A) receptors (Pharmacol Rev 50:291-313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA(A) receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. GABA(A) receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA(A) receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."

Fig. 1

Schematic rendition of a Cys-loop pentameric ligand-gated ion channel receptor. The different shades of gray signify different subunits (unspecified here), assembled in different permutations to generate multiple hetero-oligomers. The purpose of this review is to attempt to list the naturally occurring subtypes of GABA_A receptors. Similar chores face those interested in other members of the superfamily as well as other structural types of LGIC. [Adapted from Haefely W (1987) Structure and function of the benzodiazepine receptor. Chimia 41:389–396. Copyright © 1987 Swiss Chemical Society. Used with permission.]

Fig. 2

Dendrogram of the known 19 genes for human GABA_A receptors. The distances along each line are proportional to the degree of sequence identity between the different homologous subunits. The Greek letters signify subunit families of high (>70%) identity, with different Greek letter subunit families showing homology but lower sequence identity. The distances reflect the evolutionary times required to generate sufficient sequence divergence. [Reproduced from Simon J, Wakimoto H, Fujita N, Lalande M, and Barnard EA (2004) Analysis of the set of GABA_A receptor genes in the human genome. J Biol Chem 279:41422–41435. Copyright © 2004. Used with permission.]