GABAA receptor

The GABA_A receptor (GABA_AR) is an ionotropic receptor and ligand-gated ion channel. 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). Upon opening, the GABA_A receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl⁻
) and, to a lesser extent, bicarbonate ions (HCO⁻
₃).

GABA_AR are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. 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.

GABA_AR is not just the target of agonist depressants and antagonist convulsants, but most GABA_AR medicines also act at additional (allosteric) binding sites on GABA_AR proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABA_AR subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABA_AR subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABA_AR subtype-dependent transmembrane domain locations. Ethanol acts at GABA_AR subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABA_AR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.

Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl⁻
will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABA_A-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABA_B IPSP (−100 mV).

The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol), inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.

Binding of GABA to the GABAAR causes the receptor to shift from ordered lipids to clusters of PIP2 in the disordered region of the membrane. The spatial distribution of GABAAR in neurons is regulated by astrocyte derived cholesterol.

Much like the GABA_A receptor, the GABA_B receptor is an obligatory heterodimer consisting of GABA_B1 and GABA_B2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs.

The ionotropic GABA_A receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as does the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABA_A receptors. While the majority of GABA_A receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABA_A receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines, but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA_A receptors. As a result, the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site". Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABA_A receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.