GABAA Receptor

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					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 C-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 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[4], neuroactive steroids,
inhaled anaesthetics, and picrotoxin, among others.[5]

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.

      1 Target for benzodiazepines
      2 Structure and function
           o 2.1 Subunits
      3 Ligands
           o 3.1 Types
           o 3.2 Examples
           o 3.3 Effects
           o 3.4 Novel drugs
      4 See also
      5 References
      6 External links

[edit] 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).[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 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".[9]

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.[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

[edit] Structure and function

An example 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 at the α1 and γ2 interface.

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 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 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).[13][14] The endogenous ligand that binds to the benzodiazepine
receptor is inosine.

[edit] 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.[15]
In humans, the units are as follows:[16]

      six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5,
      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,[17] but rather homooligomerize
to form GABAA-ρ receptors (formerly designated as 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).[16]

The receptor binds two GABA molecules,[18] at the interface between an α and a β

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

[edit] Types

      Agonists which bind to the main receptor site (the site where GABA normally
       binds, also referred to as the "orthosteric" site) and activate it, causing increased
       Cl- conductance.
      Antagonists which 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, causing decreased Cl- conductance.
      Positive allosteric modulators which bind to an allosteric site 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 which 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.

[edit] Examples

      Agonists: gaboxadol, isoguvacine, isonipecotic acid, muscimol.
      Antagonists: bicuculline, gabazine.
      Positive allosteric modulators: barbiturates, benzodiazepines, carisoprodol,
       ethanol, etomidate, glutethimide, kavalactones[19], L-theanine, meprobamate,
       neuroactive steroids[20], nonbenzodiazepines, propofol, volatile/inhaled
      Negative allosteric modulators: cicutoxin, flumazenil, furosemide, oenanthotoxin,
       picrotoxin, Ro15-4513, thujone.

[edit] 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.[21]

[edit] 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.[22] 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)
      3-acyl-4-quinolones: selective for α1 over α3[23]

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