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 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.
GABA receptors consist of ionotropic GABAA receptors and metabotropic GABAB receptors. GABAA receptors belong to a cys-loop superfamily, which includes also inhibitory glycine receptors (GlyRs).
Functional GABAA receptors are complexes of five subunits that form a Cl- channel (ionotropic receptors). Large group of subunits (at least α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3) that can form functional receptor have been found; GABAA receptors are very heterogeneous, with differing pharmacological profiles. Activation of the chloride channel leads to Cl- influx, membrane hyperpolarization, and thus inhibition of signalling.
GABAA-ρ receptor (previous name GABAC receptor) is composed of ρ subunits only, and are metabotropic receptors like GABABR but control the Cl- channels like other GABAARs.
Postsynaptic GABAA 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 GABAA 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 GABAA 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. GABAA 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 GABAA receptors; metomidate is available as a PET radioligand [11C]MTO.
Receptor subtype specific PET tracers are under development (Lin et al., 2018).
Metabotropic GABAB receptors are coupled with G proteins and adenylate cyclase, and formed of two subunits B1 and B2. Activation of GABAB receptors can lead to activation of K+ channels or deactivation of presynaptic voltage-dependent Ca2+ channels. GABAB receptors are found both pre- and post-synaptically.
GABAB agonist baclofen is used as an antispasticity drug in MS.
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 tracers targeting GATs are under development (Sowa et al., 2018). The effects of GAT modulating drugs can be studied by assessing the displacement of [11C]flumazenil by endogenous GABA (Frankle et al., 2009).
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Updated at: 2021-12-23
Created at: 2018-05-18
Written by: Vesa Oikonen