Chloride GABAa receptors

GABAa receptors are pentameric complexes on the postsynaptic membrane with a central pore with selectivity for chloride ions. Benzodiazepines and barbiturates increase the GABA-induced chloride currents, leading to hyperpolarization of the postsynaptic membrane. 

Figure 11.5 Chloride distribution and the GABAa response. The change in membrane voltage (Fm) that results from an increase in chloride conductance following activation of GABAa receptors is determined by the resting membrane potential and the chloride equilibrium potential (Fci)- (a) Immature neurons accumulate CF via NKCC, while mature neurons possess a Cl -extruding transporter (KCC2). (b) In immature neurons GABAa receptor activation leads to CF exit and membrane depolarisation while in mature neurons the principal response is CF entry and h5q)erpolarisation. This is the classic inhibitory postsynaptic potential (IPSP)...

Experimentally all GABA antagonists induce convulsions. These include the genuine receptor antagonist bicuculline, which competes with GABA for its recognition site on the GABAa receptor and picrotoxin, which binds to a different site more closely related to the chloride ion channel. 

GABAa receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors 293 A family of pentameric GABAA-receptor protein subtypes exists 294 The GABAa receptor is the major molecular target for the action of many drugs in the brain 296... 

GABAa receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

There are now indications for the interaction of progesterone metabolites with the Cl channel of the GABAa receptor (Fig. 52-7). The A-ring-reduced steroids, especially those with the 5a,3a configuration, are particularly active on the GABAa receptor [ 12]. By facilitating chloride-channel opening, these steroids produce anesthetic, anxiolytic and sedative-hypnotic effects (see Ch. 16). 

Westh-Hansen, S. E., Witt, M. R., Dekermendjian, K., Liljefors, T., Rasmussen, P. B., and Nielsen, M. (1999) Arginine residue 120 of the human GABAa receptor ai, subunit is essential for GABA binding and chloride ion current gating. NeuroReport 10, 2417-2421. 

Ito Y, Segawa K, Fukuda H. (1995). Functional diversity of GABAA receptor ligand-gated chloride channels in rat synaptoneurosomes. Synapse. 19(3) 188-96. 

Mehta AK, Ticku MK. (1989). Benzodiazepine and beta-carboline interactions with GABAA receptor-gated chloride channels in mammalian cultured spinal cord neurons. J Pharmacol Exp Then 249(2) 418-23. 

In the retina, homomeric receptors consisting of the p-subunit represent a particular class of GABA-gated chloride channels. Their GABA site is insensitive to bicuculline and baclofen and they are not modulated by barbiturates or benzodiazepines. Due to these distinctive features, the receptors are sometimes termed GABAc receptors (Bormann 2000), although they are be considered a homomeric class of GABAa receptors (Barnard et al. 1998). 

The GABAA-receptor-chloride ionophore sites of drug action. 

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