GABA_A receptors

The GABA_A receptors activation opens a channel selective for the Cl^-. However this generally results in an ipsp, in a few neurons, particularly in the embryo, the internal chloride concentration is very high that the chloride reversal potential is closer to zero than the resting potential. In these situations GABA generates an epsp; that is it is excitatory.

The GABA_A receptors are pentamers of diverse combinations of subunits designated α1–α6, β1–β3, γ1–γ3, δ, ?, θ and ρ1–ρ3 (Note that in spite of sharing the similar nomenclature, these subunits are not similar as those in the nAChR). However a large number of receptors could in theory be assemble from these only 11 have been positively specified so far. The GABA-binding site is structurally alike to the acetylcholine-binding site, with two molecules of the GABA acting allosterically to open the channel.

A variety of GABA_A receptors hold binding sites for endogenous agents (i.e., endozepines and neurosteroids) and numerous major classes of drugs (i.e., benzodiazepines, barbiturates, ethanol, & volatile anesthetics). Such compounds bind to a range of sites distinct from the GABA-binding site and act by allosterically modifying the binding of GABA and thereby modulating the chloride current.

Usual benzodiazepines, (example, diazepam) are agonists of the benzodiazepine-binding site. On binding they increase the affinity of the receptor for GABA that causes the chloride channel to open more often. The overall effect is to potentiate the inhibitory result of GABA without prolonging it. That diazepam exerts its anti-anxiety and muscle relaxant effects through receptors containing α2 subunits, but it’s sedative and anti-convulsant effects throughout α1-containing receptors, displays the significance of subunit makeup.

The Benzodiazepines have a position in the short-term treatment of anxiety (the dependence is seen with long-term use) and as sedatives or basal anesthetics in minor surgery. Most of the benzodiazepines are too sedative to be used for the maintenance therapy in epilepsy, however intravenously they can be life-saving in the severe seizures.

The Inverse agonists bind the BZ site and reduce channel opening. Not amazingly they have the unpleasant pharmacological profile of being and pro-convulsant. The Endogenous inverse agonists at the BZ site have been specified. Endozepines are the peptides inhibitor released by astrocytes. At GABA_A receptors they increase the anxiety. Additionally they bind to G-protein-coupled receptors. Such mediate anorexigenic effects of the endozepines by acting on NPY/AgRP and POMC/CART (proopiomelanocortin/cocaine- and amphetamine-related transcript) neurons in the hypothalamus.

The Neurosteroids are endogenous steroids active in the brain and involve pregnenolone and dehydroepiandrosterone and their sulfates. The Neurosteroids are formed in the peripheral and central nervous system by the glial cells and neurons, but supplemented by the gonadal and adrenal steroids that easily cross the blood–brain barrier. They are formed during stress, rise during the luteal phase of the menstrual cycle, and reach at high concentrations in the pregnancy. The Neurosteroids act on GABA_A and NMDA (N-methyl-d-aspartate) receptors. At GABA_A receptors they potentiate GABA-activated currents. The Neurosteroids are anticonvulsant, anxiolytic, and possibly the antidepressant.