GABA A receptor

The GABAA receptor is one of the three ligand-gated ion channels responsible for mediating the effects of Gamma-AminoButyric Acid (GABA), the major inhibitory neurotransmitter in the human body.

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 chloride ion concentration is high outside the cell, opening of the channel pore results in an influx of chloride into the cell, thus making it more negative (hyperpolarizing it). The GABAA channel opens quickly and thus contributes to the early part of the inhibitory postsynaptic potential (IPSP) (Siegel et al., 1999; Chen et al., 2005).

Subunits
There are numerous subunit isoforms for the GABAA receptor, which determine the receptor’s agonist affinity, chance of opening, conductance, and other properties (Cossart et al., 2005). There are six types of &alpha; subunits, three &beta;'s, three &gamma;'s, as well as a &delta;, an &epsilon;, a &pi;, a &theta;, and three ρs (Martin and Dunn, 2002; Sieghart et al., Neurochem Int 1999;34:379–85). Five subunits can combine in different ways to form GABAA channels, but the most common type in the brain has two &alpha;'s, two &beta;'s, and a &gamma; (Martin and Dunn, 2002). The receptor binds two GABA molecules (Siegel et al., 1999; Colquhoun and Sivilotti, 2004), somewhere between an &alpha; and a &beta; subunit (Martin and Dunn, 2002).

Agonists and antagonists
Other ligands (besides GABA) interact with the GABAA receptor to activate it (agonists), to inhibit its activation (antagonists) or to increase or decrease its response to an agonist (positive and negative allosteric modulators). Such other ligands include benzodiazepines (increase pore opening frequency; often the ingredient of sleep pills and anxiety medications), barbiturates (increase pore opening duration; used as sedatives), and certain steroids, called neuroactive steroids.

Among antagonists are picrotoxin (which blocks the channel pore) and bicuculline (which occupies the GABA site and prevents GABA from activating the receptor). The antagonist flumazenil is used medically to reverse the effects of the benzodiazepines.

A useful property of the many agonists and some antagonists is that they often have a greater interaction with GABAA receptors which contain 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 combintations may be responsible for behavioral effects of drugs acting at GABAA receptors. Among the behavioral effects of such drugs are relief of anxiety (anxiolysis), muscle relaxation, sedation, anticonvulsion, and anesthesia.