GABAA receptor

The GABA_A receptor is one of two ligand-gated ion channels responsible for mediating the effects of Gamma-Amino Butyric Acid (GABA), the major inhibitory neurotransmitter in the brain. The GABA_A receptor complex is also the molecular target of the benzodiazepine class of tranquilizer drugs, and hence it is also often referred to as the benzodiazepine receptor (although the benzodiazepines do not bind to the same receptor site as the endogenous ligand, GABA).

In addition to the GABA and benzodiazepine binding sites, the GABA_A receptor complex appears to have distinct binding sites for furosemide, neuroactive steroids, picrotoxin, barbiturates, ethanol, kavalactones, GHB, and inhalation anesthetics^[1]

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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 at a synapse. 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 ions (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 GABA_A receptors tends to stabilize 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 GABA_A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).^[2][3] The endogenous ligand that binds to the benzodiazepine receptor is inosine.

Subunits

GABA_A 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 GABA_A receptor, which determine the receptor’s agonist affinity, chance of opening, conductance, and other properties.^[4]

In humans, the units are as follows:^[5]

• 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 GABA_A units listed above,^[6] but rather homooligomerize to form GABA_C receptors.

Five subunits can combine in different ways to form GABA_A channels, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α₂β₂γ).^[5]

The receptor binds two GABA molecules,^[7] at the interface between an α and a β subunit.^[5]

Agonists, antagonists, and inverse agonists

Other ligands (besides GABA) interact with the GABA_A receptor to increase chloride conductance (agonists), decrease conductance (inverse agonists) or to bind to the receptor and have no effect other than to prevent the binding of agonists or inverse agonists (antagonists). Hence ligands for the GABA_A receptor span a range of effects from full agonism to antagonism to inverse agonism.

Agonists

Full agonists display a large number of effects including anti-anxiety (anxiolytic), muscle relaxant, sedation, anti-convulsion, and at high enough doses, anesthesia. Partial agonists may display a subset of these properties (for example anxiolytic without sedation).

Such other agonist ligands include

• benzodiazepines (increase pore opening frequency; often the active ingredient of sleep pills and anxiety medications)
• nonbenzodiazepines (newer class of sleep / anti-anxiety medications)
• barbiturates (increase pore opening duration; used as sedatives)
• kavalactones (psychoactive compunds found in the roots of the kava plant)^[8]
• certain steroids, called neuroactive steroids^{[9] [10] [11] [12] [13] [14] [15] [16] [17] [18]}

Muscimol is an agonist used to distinguish GABA_A from the GABA_B receptor.

Antagonists

Among antagonists are

• picrotoxin (non-competitive; binds the channel pore, effectively blocking any ions from moving through it)
• bicuculline (competitive; transiently occupies the GABA binding site, thus preventing GABA from activating the receptor)

The antagonist flumazenil is used medically to reverse the effects of the benzodiazepines.

Inverse agonists

Full inverse agonists have convulsive properties while partial inverse agonists may be useful as aids in memory and learning. An example of a partial inverse agonist is Ro15-4513.

Subtype selective ligands

A useful property of the many benzodiazepine receptor ligands is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABA_A 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 GABA_A receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic affects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, but some examples of these compounds which are widely used in scientific research are Bretazenil (subtype-selective partial agonist), Imidazenil (partial agonist at some subtypes, weak antagonist at others) and QH-ii-066 (full agonist highly selective for α₅ subtype).

See also

• GABA receptor
• GABA_B receptor
• GABA_C receptor
• Glycine receptor

References