GABAergic system

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter, while glutamate, from which GABA is synthesized by the enzyme L-glutamic acid decarboxylase (GAD), is an excitatory and most abundant neurotransmitter in the nervous system. GABAergic system involves the biosynthesis and metabolic degradation of GABA, its release and interaction with receptors, and its inactivation by high-affinity transport systems in GABAergic and glutamatergic neurons and astrocytes.

GABA has important functions also in peripheral organs, including gastrointestinal tract, adrenal medulla, pancreas, and immune cells.

GABA synthesis and degradation

GABA is synthesized by the enzyme L-glutamic acid decarboxylase, the two forms of which (GAD₆₅ and GAD₆₇) are encoded for by two independent genes. Coenzyme pyridoxal phosphate (formed from vitamin B6) is needed for the activity of the GADs; most of GAD₆₅ (mainly found in nerve endings) is in inactive state, and activated by phosphorylation; most of GAD₆₇ (cytosolic enzyme) is in active state, and inhibited by phosphorylation. GABA is stored in synaptic vesicles; exocytosis is triggered by increase in cytosolic [Ca²⁺].

Astrocytes collect GABA that is released from GABAergic neurons, and convert it to glutamine. Astrocytes release glutamine, and GABAergic neurons collect it and convert it to glutamate and back to GABA. GABA transaminase (GABA-T) catabolizes GABA, and is found in the mitochondrial matrix of most cells; like GAD, it needs the coenzyme pyridoxal phosphate.

Pancreatic islets can produce large quantities of GABA; it suppresses glucagon secretion in the α-cells, and increases insulin secretion in β-cells.

GABA receptors

GABA receptors consist of ionotropic GABA_A receptors and metabotropic GABA_B receptors. GABA_A receptors belong to a cys-loop superfamily, which includes also inhibitory glycine receptors (GlyRs).

GABA_A receptors

Functional GABA_A receptors are complexes of five subunits that form a Cl^- channel (ionotropic receptors). Large group of subunits (at least α_1-6, β_1-3, γ_1-3, δ, ε, θ, π, and ρ_1-3) that can form functional receptor have been found; GABA_A receptors are very heterogeneous, with differing pharmacological profiles. Activation of the chloride channel leads to Cl^- influx, membrane hyperpolarization, and thus inhibition of signalling.

GABA_A-ρ receptor (previous name GABA_C receptor) is composed of ρ subunits only, and are metabotropic receptors like GABA_BR but control the Cl^- channels like other GABA_ARs.

Postsynaptic GABA_A receptors mediate the effects of many drugs, such as benzodiazepines, barbiturates, steroids, and Zn²⁺. GABA binds at the interface between α and β subunits. Most of the drugs do not bind to the same site as GABA does, but to allosteric modulatory sites; for example benzodiazepines bind at the interface of α and γ subunits. Ethanol binds to a specific hydrophobic region and facilitates the opening of the Cl^- channel. Most of the GABA_A receptors in the central nervous system contain two α- and two β-subunits and one γ- or δ-subunit. Agonist binding leads usually to rapid desensitization of GABA_A receptors, by receptor internalization and phosphorylation.

Benzodiazepines (including diazepam, clonazepam, and flumazenil) potentiate and prolong the synaptic actions of GABA, and are used as anxiolytics, antiepileptics, and sedatives. GABA_A receptor antagonist flumazenil has been labelled with C-11 ([¹¹C]flumazenil, [¹¹C]FMZ, [¹¹C]Ro15-1788) and has been widely and successively used in brain PET imaging. In vivo human brain atlas of protein density of benzodiazepine receptor sites is based on [¹¹C]flumazenil PET (Nørgaard et al., 2021).

Metomidate is a non-barbiturate imidazole that exerts its sedative and anaesthetic action by allosteric modulation of GABA_A receptors; metomidate is available as a PET radioligand [¹¹C]MTO.

Receptor subtype specific PET tracers are under development (Lin et al., 2018).

GABA_B receptors

Metabotropic GABA_B receptors are coupled with G proteins and adenylate cyclase, and formed of two subunits B₁ and B₂. Activation of GABA_B receptors can lead to activation of K⁺ channels or deactivation of presynaptic voltage-dependent Ca²⁺ channels. GABA_B receptors are found both pre- and post-synaptically.

GABA_B agonist baclofen is used as an antispasticity drug in MS.

GABA transporters

High-affinity GABA transporters (GAT1-4) on the plasma membranes of glial cells and presynaptic neurons sequester rapidly the GABA that is released by the GABAergic neurons. Vesicular GABA transporter transports cytosolic GABA into storage vesicles.

PET radiotracers targeting GATs are under development (Sowa et al., 2018; Knippenberg et al., 2023). The effects of GAT modulating drugs can be studied by assessing the displacement of [¹¹C]flumazenil by endogenous GABA (Frankle et al., 2009).

Literature

Barragan A, Weidner JM, Jin Z, Korpi ER, Birnir B. GABAergic signalling in the immune system. Acta Physiol. 2015; 213: 819-827. doi: 10.1111/apha.12467.

Persson A, Ehrin E, Eriksson L, Farde L, Hedström CG, Litton JE, Mindus P, Sedvall G. Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatr Res. 1985; 19(4): 609-622. doi: 10.1016/0022-3956(85)90080-9.

Sequeira A, Shen K, Gottlieb A, Limon A. Human brain transcriptome analysis finds region- and subject-specific expression signatures of GABA_AR subunits. Commun Biol. 2019; 2:153. doi: 10.1038/s42003-019-0413-7.

Sigel E, Steinmann ME. Structure, function, and modulation of GABA_A receptors. J Biol Chem. 2012; 287(48): 40224-40231. doi: 10.1074/jbc.R112.386664.

Wan Y, Wang Q, Prud'homme GJ. GABAergic system in the endocrine pancreas: a new target for diabetes treatment. Diabetes Metab Syndr Obes. 2015; 8: 79-87. doi: 10.2147/DMSO.S50642.

Tags: GABA

Updated at: 2023-06-13
Created at: 2018-05-18
Written by: Vesa Oikonen