GABAA receptor

Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS).

These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure.

Thus, GABAAR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.

These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol),[7] inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.

[9] The ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs.

When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.

[18] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.

However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABAA receptors known as tonic inhibition.

Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening.

This effect during development is due to a modified Cl− gradient wherein the anions leave the cells through the GABAA receptors, since their intracellular chlorine concentration is higher than the extracellular.

[31] In the mature neuron, the GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).

[34] Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function.

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties.

[citation needed] Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.

[59] Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of the GABAA receptor mediate certain parts of the anaesthetic behavioral repertoire.

[60] A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits.

[62] There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors.

Structure of the GAB A A receptor (α1β1γ2S: PDB : 6DW1 ). Top: side view of the GABA A receptor embedded in a cell membrane . Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA A nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).
Schematic structure of the GABA A receptor. Left : GABA A monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABA A receptor) is depicted as a yellow line. Right : Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.
Schematic diagram of a GABA A receptor protein ((α1) 2 (β2) 2 (γ2)) which illustrates the five combined subunits that form the protein, the chloride ( Cl −
) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site [ 20 ]
Side view of the EM structure of the α1β3γ2 GABAA receptor. GABA and the anaesthetic etomidate are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore. [ 21 ]
GABA A receptor and where various ligands bind.
GABA bound at its orthosteric site in the beta-alpha interface of an α1β2γ2 GABAA receptor. H-atoms hidden.