Receptor ligands

GABAA receptor

The GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. In addition to the GABA binding site, the GABAA receptor complex appears to have distinct allosteric binding sites for benzodiazepines, barbiturates, ethanol, inhaled anaesthetics, furosemide, kavalactones, neuroactive steroids, and picrotoxin.

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). Whilst 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 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 GABAA 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 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 receptor is inosine.


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:

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 GABAC receptors.

Five subunits can combine in different ways to form GABAA channels, 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.


Other ligands (besides GABA) interact with the GABAA receptor complex 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 GABAA receptor span a range of effects from full agonism to antagonism to inverse agonism.


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

Such other agonist ligands include

Muscimol is an agonist used to distinguish GABAA from the GABAB receptor.


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)
  • cicutoxin and oenanthotoxin, poisons found in certain Northern Hemisphere plants that grow in boggy soils.
  • flumazenil which is used medically to reverse excessive effects of the benzodiazepines.

Inverse agonists

Full inverse agonists such as DMCM have anxiogenic and convulsant properties, while partial inverse agonists such as Ro15-4513 or subtype-selective inverse agonists such as α5IA may be useful as aids in memory and learning and as antidotes to the side effects of GABA agonists.

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 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 affects 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) and α5IA (selective inverse agonist for α5 subtype).

See also


External links

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