GABA_A receptor

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.^[4]


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.^[4]


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.^[5] 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.^[6] 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),^[7] inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.^[8]


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. ^[9]

Target for benzodiazepines[edit]

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.^[10][11] 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,^[12] 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".^[13] 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.^[14]


In order for GABA_A receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.^[15]


Different benzodiazepines have different affinities for GABA_A receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABA_A receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.^[16] Anticonvulsant effects can be produced by agonists acting at any of the GABA_A subtypes, but current research in this area is focused mainly on producing α₂-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.


The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA_A receptor, and also produces different effects on binding,^[17] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.^[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.^[19]


Also note that some GABA_A agonists such as muscimol and gaboxadol do bind to the same site on the GABA_A receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.