GABAA receptor

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Structure of the nicotinic acetylcholine receptor (nAchR: PDB: 2BG9​) which is very similar to the GABAA receptor.[1][2][3] Top: side view of the nAchR imbedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABAA nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).
Schematic structure of the GABAA receptor. Left: GABAA monomeric subunit imbedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABAA receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.

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 reversal potential of the GABAA-mediated IPSP in normal solution is −70 mV, contrasting the GABAB IPSP.

The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.[citation needed] 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, ethanol,[4] inhaled anaesthetics, and picrotoxin, among others.[5]

GABAA receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.

Target for benzodiazepines[edit]

The ionotropic GABAA 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 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.[6][7] 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,[8] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and ethanol. 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".[9]

In order for GABAA 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 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 sedative and anxiolytic effects.[citation needed]

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.[10] 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,[11] 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.[12] 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.[citation needed]

Structure and function[edit]

Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl−) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BDZ) allosteric binding site[1]

Structural understanding of the GABAA receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates.[13][14] The much sought structure of GABAA receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.[15] GABAA receptor is a pentameric transmembrane receptor that consists of five subunits arranged around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically.[16] 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).[17][18] The endogenous ligand that binds to the benzodiazepine site is inosine.[19][citation needed]

Subunits[edit]

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.[20]

In humans, the units are as follows:[21]

There are three ρ units (GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABAA units listed above,[22] but rather homooligomerize to form GABAA-ρ receptors (formerly classified as GABAC receptors but now this nomenclature has been deprecated[23] ).

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,[24] but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α1β2γ2).[21]

The receptor binds two GABA molecules,[25] at the interface between an α and a β subunit.[21]

Ligands[edit]

A number of ligands have been found to bind to various sites on the GABAA receptor complex and modulate it besides GABA itself.[which?] A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types[edit]

  • Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl− conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl− conductance.
  • Allosteric agonists: bind to allosteric sites on the receptor and activate the receptor in absence of orthosteric ligands.
  • First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl− conductance. SAMs do not affect the conductance, but occupy the binding site.
  • Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.
  • Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.[26]
  • Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl− conductance through the ion channel.

Examples[edit]

Effects[edit]

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol and the z-drugs may also be hallucinogenic.[citation needed] Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.[citation needed] 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.[33]

Novel drugs[edit]

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.[34] 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[35]

Distribution[edit]

As GABAA receptors are responsible for most of the physiological activities of GABA in the central nervous system, subunits are expressed in many parts of the brain. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. In neurons themselves, the type GABAA receptor subunits and their densities can vary between cell bodies and dendrites.[36] Interestingly, GABAA receptors can also be found in other tissues, including leydig cells, placenta, immune cells, liver, bone growth plates and several other endocrine tissues. Subunit expression varies between 'normal' tissue and malignancies and GABAA receptors can influence cell proliferation.[37]

See also[edit]

References[edit]

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External links[edit]

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