A half century of γ-aminobutyric acid

Abstract

γ-aminobutyric acid has become one of the most widely known neurotransmitter molecules in the brain over the last 50 years, recognised for its pivotal role in inhibiting neural excitability. It emerged from studies of crustacean muscle and neurons before its significance to the mammalian nervous system was appreciated. Now, after five decades of investigation, we know that most neurons are γ-aminobutyric-acid-sensitive, it is a cornerstone of neural physiology and dysfunction to γ-aminobutyric acid signalling is increasingly documented in a range of neurological diseases. In this review, we briefly chart the neurodevelopment of γ-aminobutyric acid and its two major receptor subtypes: the γ-aminobutyric acid_A and γ-aminobutyric acid_B receptors, starting from the humble invertebrate origins of being an 'interesting molecule' acting at a single γ-aminobutyric acid receptor type, to one of the brain's most important neurochemical components and vital drug targets for major therapeutic classes of drugs. We document the period of molecular cloning and the explosive influence this had on the field of neuroscience and pharmacology up to the present day and the production of atomic γ-aminobutyric acid_A and γ-aminobutyric acid_B receptor structures. γ-Aminobutyric acid is no longer a humble molecule but the instigator of rich and powerful signalling processes that are absolutely vital for healthy brain function.

Keywords: GABA; GABAA receptor; GABAB receptor; inhibition.

Figure 1.

GABA-mediated inhibitory postsynaptic potentials (IPSPs) recorded from neocortical neurons: (a) Hyperpolarizing IPSP with two superimposed current steps (I, top trace) deflecting the membrane potential (V, arrow, blue dotted line, lower trace) before the IPSP and then at the peak IPSP. Note the reduction in the voltage step size during the IPSP, which is indicative of increased membrane conductance caused by synaptic release of GABA and the opening of GABA ion channels. Red dotted lines indicate the extent of hyperpolarisation. (b) Application of GABA also produces a hyperpolarisation of the membrane with increased membrane conductance (note that both voltage steps are now equally reduced due to GABA application). Note also the occlusion of the IPSP. Data in (a) and (b) are modified after being taken from Dreifuss et al (1969).

Figure 2.

Structural architectures of GABA_A receptor subunits: (a) Representation of the GABA receptor β3 homomer crystal structure showing the extracellular domain (ECD) and transmembrane domain (TMD) as seen from the plane of the cell membrane (PDB, 4cof, Miller and Aricescu, 2014). Each β3 subunit comprising the pentamer is shown in a different colour. Secondary structures are shown – β sheets in the ECD and α helices in the TMD. (b) A flattened and simplified schematic of a typical GABA_A receptor subunit showing structures for the extracellular domain (ECD, β sheets), the transmembrane domain (TMD) with four α-helices, M1-M4, and the unknown structure of the intracellular domain (ICD) with phosphorylation sites (red circles). The key structures involved in receptor activation, loops 2, 7 and 9 are shown including loop C which is close to the GABA binding site. Modified from a schematic in Smart and Paoletti, 2012. (c) Plan view of a GABA_A receptor pentamer schematic showing subunit arrangement and the principal (+) and complementary (–) subunit interfaces as well as the position of the M1-M4 α-helices in the γ2 subunit only. GABA and benzodiazepine interfacial binding locations are shown.

Figure 3.

Subunit composition of native GABA_A receptors. The three lists are designed with minor modifications in terms of assignments from Table 3 in Olsen and Sieghart (2008) showing the likeliest combinations of GABA_A receptors subunits that are thought to exist in the mammalian brain. The probability of existence of a receptor in the brain is considered highest in the left panel and less so in the middle to right panels. x and y signify that different copies of α and β subunits may co-assemble in the same receptor pentamer.

Figure 4.

Cellular expression profiles of GABA_A receptors subunits. The text boxes show the major sites of expression of GABA_A receptor α subunits that are also depicted in diagrammatic form in the schematic parasagittal section through the brain. The relative sizes of the spheres indicate the extent of GABA_A receptor α subunit expression. Data have been accrued from numerous immunofluorescence studies, and mostly taken as a collation from (Fritschy and Brunig, 2003).

Figure 5.

Structures of the GABA_A receptor: (a) Shows a chimeric GABA_A receptor composed of an extracellular domain (orange) from GLIC and transmembrane domain from the GABA_A receptor α1 subunit (green). Note GLIC is a homomer and allows the expression of a pentamer of α1 subunit TMDs. Schematic based on study by Laverty et al., 2017. (b) Cryo-EM structure of an α1β3γ2L GABA_A receptor in ribbon format. The α1 subunits are red, β3 subunits are green and the γ2L subunit is yellow; the nanobody used to isolate the receptor protein (blue). Note the resolution of the initial part of the ICD. Images are taken from the protein databank (PDB 6I53) (Laverty et al., 2019).