GABAA receptor

The GABAA receptor (GABAAR) 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. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.

The active site of the GABAA 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, barbiturates, ethanol, neuroactive steroids, inhaled anaesthetics, and picrotoxin, among others.

Mild inhibition of neuronal firing by drugs acting at the GABAA receptor causes a reduction of anxiety in the patient (an anxiolytic effect) while more pronounced inhibition induces sleep (sedation) and in extreme cases of overdose, may result in death.

Target for benzodiazepines
The ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepine (BZ) class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as 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 GABAA receptors (see figure to the right). While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive there exists a minority of GABAA 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 the neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABAA 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".

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA 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 sedatory and anxiolytic effects.

Different benzodiazepines have different affinities for GABAA 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 GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity. Anticonvulsant effects can be produced by agonists acting at any of the GABAA 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 GABAA receptor, and also produces different effects on binding, with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer. 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.

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

Structure and function


The receptor is a multimeric transmembrane receptor that consists of five subunits arranged around a central pore. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically. The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl−) to pass down an electrochemical gradient. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABAA receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect is typically inhibitory, reducing the activity of the neuron. The GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP). The endogenous ligand that binds to the benzodiazepine site is inosine.

Subunits
GABAA receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 receptor. There are numerous subunit isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.

In humans, the units are as follows:
 * six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)
 * three β's (GABRB1, GABRB2, GABRB3)
 * three γ's (GABRG1, GABRG2, GABRG3)
 * as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ)

There are three ρ units (GABRR1, GABRR2, GABRR3), however these do not coassemble with the classical GABAA units listed above, but rather homooligomerize to form GABAA-ρ receptors (formerly designated as GABAC receptors).

Five subunits can combine in different ways to form GABAA channels. The minimal requirement to produce a GABA-gated ion channel is the inclusion of both α and β subunits, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α2β2γ).

The receptor binds two GABA molecules, at the interface between an α and a β subunit.

Ligands
A number of ligands have been found to bind to various sites on the GABAA receptor complex and modulate it besides GABA itself.

Types

 * Agonists: Bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site) and activate it, resulting in increased Cl- conductance.
 * Antagonists: Bind to the main receptor site but do not activate it. Though they have no effect on their own, antagonists compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl- conductance.
 * Positive Allosteric Modulators: Bind to allosteric sites on the receptor complex and affect it in a positive manner, causing increased efficiency of the main site and therefore an indirect increase in Cl- conductance.
 * Negative Allosteric Modulators: Bind to an allosteric site on the receptor complex and affect it in a negative manner, causing decreased efficiency of the main site and therefore an indirect decrease in Cl- conductance.
 * Uncompetitive Channel Blockers: Bind to or near the central pore of the receptor complex and directly block Cl- conductance through the ion channel.

Examples

 * Agonists: GABA, Gaboxadol, Ibotenic Acid, Muscimol, Progabide.
 * Antagonists: Bicuculline.
 * Positive Allosteric Modulators: Barbiturates, Benzodiazepines, Carisoprodol, Ethanol (Alcohol), Etomidate, Glutethimide, Kavalactones, Meprobamate, Methaqualone, Neuroactive Steroids,(a) ; (b) ; (c); (d) ; (e) ; (f) ; (g) ; (h) ; (i) ; (j) Niacin/Niacinamide, Nonbenzodiazepines, Propofol, Theanine, Valerenic Acid, Volatile/Inhaled Anesthetics.
 * Negative Allosteric Modulators: Flumazenil, Gabazine, Ro15-4513, Sarmazenil.
 * Non-competitive Channel Blockers: Cicutoxin, Oenanthotoxin, Pentylenetetrazol, Picrotoxin, Thujone, Lindane

Effects
Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol may also be hallucinogenic. Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion. Some of the subtype-selective negative allosteric modulators such as α5IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs.

Novel drugs
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. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:


 * CL-218,872 (highly α1-selective agonist)
 * bretazenil (subtype-selective partial agonist)
 * imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)
 * QH-ii-066 (full agonist highly selective for α5 subtype)
 * α5IA (selective inverse agonist for α5 subtype)
 * SL-651,498 (full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5
 * 3-acyl-4-quinolones: selective for α1 over α3