The 5-Containing GABAA Receptorsa Brief Summary

GABA(A) receptors are the major inhibitory neurotransmitter receptor in the human brain. The receptors are assembled from combination of protein subunits in pentameric complex which may consist of 1-6, 1-3, 1-3, 1-3, , epsilon, , or subunits. There are a theoretical >150,000 possible assemblies and arrangements of GABA(A) subunits, although only a few combinations have been found in human with the most dominant consists of 21, 22, and 12 in a counterclockwise arrangement as seen from the synaptic cleft. The receptors also possess binding sites for various unrelated substances including benzodiazepines, barbiturates, and anesthetics. The 5-containing GABA(A)Rs only make up 5% of the entire receptor population, but up to 25% of the receptor subtype is located in the crucial learning and memory-associated area of the brainthe hippocampus, which has ignited myriads of hypotheses and theories in regard to its role. As well as exhibiting synaptic phasic inhibition, the 5-containing receptors are also extrasynaptic and mediate tonic inhibition with continuously occurring smaller amplitude. Studies on negative-allosteric modulators for reducing this tonic inhibition have been shown to enhance learning and memory in neurological disorders such as schizophrenia, Down syndrome, and autism with a possible alternative benzodiazepine binding site. Therefore, a few 5 subunit-specific compounds have been developed to address these pharmacological needs. With its small population, the 5-containing receptors could be the key and also the answer for many untreated cognitive dysfunctions and disorders.