A GABAa Receptors

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Most neurons express GABAA receptors. GABAA receptors are GABA-gated chloride channels located on the postsynaptic membrane. Upon binding GABA, the channel opens and chloride flows along its concentration gradient. The extracellular chloride concentration is usually higher than the intracellular concentration, so chloride usually flows into the cell. The inward chloride flux results in hyperpolarization of the postsynaptic membrane and a concomitant decrease in the probability of cell firing. In some cases, however, GABA evokes a depolarizing response, either because of high intracellular chloride concentrations resulting in an outward flow of chloride through the open channel or because of the flow of bicarbonate ions through the channel.

Gaba Cycle

Figure 4 The GABA shunt. GABA can contribute to the TCA cycle via the GABA shunt, which converts a-ketoglutarate to succinate. The GABA shunt provides less energy than the complete TCA cycle because it bypasses the formation of one NADH and one GTP. Nonetheless, approximately 10-20% of TCA cycle activity in most brain regions is provided by the GABA shunt. SSA, succinic semialdehyde; SSADH, succinic semialdehyde dehydrogenase.

Figure 4 The GABA shunt. GABA can contribute to the TCA cycle via the GABA shunt, which converts a-ketoglutarate to succinate. The GABA shunt provides less energy than the complete TCA cycle because it bypasses the formation of one NADH and one GTP. Nonetheless, approximately 10-20% of TCA cycle activity in most brain regions is provided by the GABA shunt. SSA, succinic semialdehyde; SSADH, succinic semialdehyde dehydrogenase.

1. GABAa Receptor Topology

GABAa receptors are highly diverse. Each GABAa receptor consists of five transmembrane polypeptide subunits. At least 19 subunits exist, named a(1-6), b(1-4), g(1-3), d, e, p(1-3), and p. The recently identified subtype 6 may be identical to b4. Splice variants of several subunits exist as well. Receptor heterogeneity results from at least 20 different combinations of five subunits.

Each subunit consists of a long extracellular amino-terminal region, four transmembrane domains, and a large intracellular loop between the third and fourth transmembrane domains (Fig. 5A). This motif is shared by the channel superfamily that includes nicotinic acetylcholine receptors, glycine receptors, and serotonin 5-HT3 receptors. Five subunits form a complex with a central pore (Fig. 5B). The amino-terminal domains of the a and b subunits are believed to be exclusively responsible for the GABA binding site. Receptor gating is almost certainly mediated by the M2 regions of all five subunits, which presumably line the pore, as is the case in related receptors.

2. GABAa Subunit Composition

The GABAa subunit genes are located on several chromosomes. For example, human a1 is located on chromosome 5, a2 on chromosome 4, and a5 on chromosome 15. Many of the subunit genes occur in clusters. For instance, a1/a6/P2/y2 are clustered on

Human Gabaa

Figure 5 GABAA receptor subunit and complex topology. (A). Each GABAA subunit has four transmembrane domains (M1-M4). The amino terminus is extracellular and the carboxy terminus is intracellular. (B). Top view of five subunits that form the receptor complex with a central pore, which is likely lined by the M2 domains of each subunit [reprinted from Cherubini and Conti, TINS 24(3), 155-162, 2001, with permission of Elsevier Science].

Figure 5 GABAA receptor subunit and complex topology. (A). Each GABAA subunit has four transmembrane domains (M1-M4). The amino terminus is extracellular and the carboxy terminus is intracellular. (B). Top view of five subunits that form the receptor complex with a central pore, which is likely lined by the M2 domains of each subunit [reprinted from Cherubini and Conti, TINS 24(3), 155-162, 2001, with permission of Elsevier Science].

chromosome 5, whereas a2/a4/b1/g1 are located on chromosome 4. The chromosomal arrangement of the subunit genes suggests that both gene and cluster duplication occurred during evolution.

Despite the number of potential subunit combinations, there are some common combinations, which are summarized in Table II. Both development and brain region regulate GABAa subunit composition and presumably each combination has unique properties based not only on each subunit but also on the assembly as a whole. The functional consequences of specific combinations are not well understood but can affect both receptor function and location.

The subunit composition affects receptor binding of GABA and other ligands, but it is also important in receptor targeting, assembly, and clustering. For instance, g2 knockout mice show reduced GABAa receptor clustering as well as reduced ligand binding. a6 knockout mice also demonstrate decreased d subunit expression, despite normal mRNA levels, indicating posttranscriptional control by the subunits.

3. Pharmacology of GABAa Receptors

The GABAa receptor is affected by a myriad of drugs, including those that both cause and prevent convulsions, those that relieve anxiety, and those that relax, sedate, and anesthetize. Receptor subunit composition is critical in determining drug action. The specific binding sites for many but not all compounds have been identified.

Benzodiazepines (BZs) constitute a class of drugs that act on the GABAA receptor with sedative, anxiolytic (antianxiety), muscle relaxant, and cognitive effects. BZs bind to the external surface of receptors with specific combinations of subunits: A combination of g2 with a1, a2, a3, or a5 and any b subunit confers BZ binding. Each a subunit may have its own BZ binding affinity. The BZ binding site is thought to be between the g2 and a subunits and is highly homologous to the GABA-binding site located between the a and b subunits. Recent work has shown that the a1 subunit mediates the sedative but not the anxiolytic effect of BZs.

Anticonvulsant and anesthetic drugs can positively or negatively modulate the receptor response to GABA. For example, barbiturates can directly enhance the GABA response either by opening the chloride channel or by increasing the time for which it remains open after binding to GABA. Very high concentrations of barbiturates can block the channel entirely, however. Barbiturates bind within the GA-BAA receptor pore and can also act at other receptors, including glutamate and acetylcholine receptors. This

Table II

Common GABAa Receptor Subtype Combinations and Their Locations"

Subtype

<*4bxg2

<*5b3g2

a2├čigi

g3-containing receptors e-containing receptors

Approx 50% of the total GABAA receptors; widespread; GABAergic interneur-ons

Approx 15-20% of total GABAA receptors; cortex, hippocampus, amygdala, septum, hypothalamus

Approx 15-20% of total GABAA receptors; cortex, amygdala, septum, raphe; monoaminergic, serotonergic neurons

< 5% of total GABAA receptors in whole brain; cortex, hippocampus, thalamus, striatum

< 5% of total GABAA receptors in whole brain; cortex, hippocampus, thalamus, striatum

< 5% of total GABAA receptors in whole brain; hippocampus (approx 20% of total GABAA receptors), cortex

< 5% of total GABAA receptors in whole brain; cerebellar granule cells (30-40% of total GABAA receptors)

< 5% of total GABAA receptors in whole brain; cerebellar granule cells (20-30% of total GABAA receptors); extrasynap-tic

< 10% of total GABAA receptors in whole brain; limbic regions, basal ganglia, tyrosine hydroxylase-positive neurons, Bergmann glia

< 5% of total GABAA receptors in whole brain; widespread, low abundance; little data available

< 5% of total GABAA receptors in whole brain; hippocampus, hypothalamus; little data available aAdapted from P. J. Whiting, K. A. Wafford, and R. M. McKernan, Pharmacologic subtypes of GABAa receptors based on subunit composition. In GABA in the Nervous System: The View at Fifty Years. (D. L. Martin and R. W. Olsen, Eds.). Lippincott, Williams & Wilkins, Philadelphia (2000).

may reflect conservation of specific residues within the subunits. The anesthetic binding site is different from the GABA binding site, and it is probably located within the pore.

Alcohol acts on the GABAa receptor, although its route of action and potential binding site are unclear. In some cases, alcohol potentiates GABA function at the GABAa receptor, but this effect may depend on receptor subtypes or on an indirect action. Currently, there appear to be alcohol-sensitive and alcohol-insensitive GABAa receptors, but the basis for that sensitivity is unclear.

neurotransmitter and also decreases the action potential duration. Postsynaptic GABAB receptor activation causes inwardly rectifying K+ channels to open, which increases K+ conductance. Increased K + conductance causes an increase in extracellular K + and a concomitant hyperpolarization, rendering Na + channels inactive. Thus, the net result of GABA binding to GABAB receptors is a decrease in the probability of cell firing.

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