GABA(A) Receptors: Various Stoichiometrics of Subunit Arrangement in alpha 1 beta 3 and alpha 1 beta 3 epsilon Receptors

GABA(A) receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including alpha 1-6, beta 1-3, gamma 1-3, delta, epsilon, pi, theta and rho 1-3. The majority of receptors are comprised of alpha, beta and gamma or delta subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are alpha 1 beta gamma 2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to alpha beta gamma, the binary alpha beta receptors lack a benzodiazepine alpha-gamma 2 interface. In pentameric alpha beta receptors, the third subunit is replaced with either an alpha 1 or a beta 3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2 alpha: 3 beta or 3 alpha: 2 beta. The consequence of this is that 3 alpha: 2 beta receptors contain an alpha-alpha interface whereas 2 alpha: 3 beta receptors contain a beta-beta interface. Apart from the replacement of. by alpha 1 or beta 3 in binary receptors, the incorporation of e subunit into GABAA receptors might be more complicated. As the e subunit is not only capable of substituting the. subunit, but also replacing the alpha/beta subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.