Structure, function, and modulation of GABA(A) receptors

Abstract

The GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABA(A) receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABA(A) receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects.

FIGURE 1.

Phylogenetic tree analysis of the 19 known genes coding for human GABA_A receptor subunits. The immature amino acid sequences were obtained from the UniProt database (94). The alignment was done with ClustalX (95), and Dendroscope (64) was used for depiction of the dendrogram.

FIGURE 2.

Schematic representation of the major isoform of GABA_A receptors, α₁β₂γ₂. The GABA_A receptors are integral membrane proteins. Five subunits are grouped around the central ion pore. A, topology of a single subunit. All subunits share this topology. B, top view of the pentamer. The sidedness of the subunits is symbolized + and −.

FIGURE 3.

Possible arrangements in a pentamer of subunits taken from three different types, α (yellow), β (red), and γ (green). There are three homomeric receptors, 18 receptors composed of two subunits, and 30 receptors composed of three different subunits. The receptor on the blue square represents the current consensus of the subunit arrangement in α₁β₂γ₂ GABA_A receptors as seen from the cell exterior.

FIGURE 4.

A, current trace of an electrophysiological recording showing an application of GABA to a cell expressing GABA_A receptors. Positive allosteric modulators of the benzodiazepine type (in this case, 1 μm diazepam) do not induce any current by themselves but increase the current amplitude upon co-application with low concentrations of the agonist GABA. B, GABA concentration response curves in the absence (EC₅₀ = 20 μm, n = 1.5) and presence (EC₅₀ = 10 μm, n = 1.5) of diazepam. The maximal current amplitude (100%) is not affected by diazepam. The dashed line shows GABA concentration dependence of the calculated relative current stimulation. Please note that there is no stimulation at high concentrations of GABA.