The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebrate central nervous system.
There are two classes of GABA receptors:
- GABAA : GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors)
- GABAB : GABAB receptors are G protein-coupled receptors (also known as metabotropic receptors).
The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is a heteromer composed of five subunits, most commonly two α's, two β's and one γ (α2β2γ). For each subunit, many subtypes exist (α1-6, β1-3 and γ1-3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects. Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue.
Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedatory and anxiolytic effects. Furthermore, different benzodiazepines can have different affinities for BzRs made up of different collection of subunits. For instance, those with high activity at the α1 are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.
Protein Aminoacids Percentage
GABAB receptors are metabotropic transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels.
These receptors are found in the central and peripheral autonomic nervous system.
Protein Aminoacids Percentage
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:9872744, PubMed:10906333, PubMed:10773016). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744, PubMed:22660477). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:9872316, PubMed:10075644, PubMed:9872744, PubMed:22660477). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable).
Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction, 2012
- It plays a neuromodulatory role in maintaining the balance of excitation and inhibition by a series of ion channel and receptor-mediated effects, which results in upregulation the γ-amino butyric acid (GABA) B receptor (GABABR) and increased K+ conductance.
Regulation of GABAA Receptor Subunit Expression by Pharmacological Agents, 2010
The γ-aminobutyric acid (GABA) type A receptor system, the main fast-acting inhibitory neurotransmitter system in the brain, is the pharmacological target for many drugs used clinically to treat, for example, anxiety disorders and epilepsy, and to induce and maintain sedation, sleep, and anesthesia. These drugs facilitate the function of pentameric GABAA receptors that exhibit widespread expression in all brain regions and large structural and pharmacological heterogeneity as a result of composition from a repertoire of 19 subunit variants. One of the main problems in clinical use of GABAA receptor agonists is the development of tolerance. Most drugs, in long-term use and during withdrawal, have been associated with important modulations of the receptor subunit expression in brain-region-specific manner, participating in the mechanisms of tolerance and dependence. In most cases, the molecular mechanisms of regulation of subunit expression are poorly known, partly as a result of neurobiological adaptation to altered neuronal function. More knowledge has been obtained on the mechanisms of GABAA receptor trafficking and cell surface expression and the processes that may contribute to tolerance, although their possible pharmacological regulation is not known. Drug development for neuropsychiatric disorders, including epilepsy, alcoholism, schizophrenia, and anxiety, has been ongoing for several years. One key step to extend drug development related to GABAA receptors is likely to require deeper understanding of the adaptational mechanisms of neurons, receptors themselves with interacting proteins, and finally receptor subunits during drug action and in neuropsychiatric disease processes.