Barbiturate binding site

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

Figure 4.1 Benzodiazepines interact with the GABA receptor in the brain and activate the ceii membrane of neurons to open and allow negative chioride ions (Cl ) to enter the neuron (a, ), y subunits form the Cl- ion). This entry inhibits that neuron s ability to fire an action potential. The GABA receptor also has binding sites for other substances, such as steroids, barbiturates, and alcohol.

The GABAj receptor is a protein complex that mediates neuronal inhibition throughout the central nervous system. The inhibitory neurotransmitter GABA and various substances, including benzodiazepines, neurosteroids, barbiturates, and alcohol, all have binding sites on it (Figure 29-1). 

Our knowledge of the binding sites of the other ligands at the GABA receptor is more limited. The barbiturates and neurosteroids act through distinct binding sites, but the specific subunits involved have not been clearly determined. Unlike the benzodiazepines, they do not seem to require the y subunit to function and may just require a and (5 subunits. 

Like benzodiazepines, barbiturates bind to the GABA receptor— however, at a different site from the benzodiazepines. Measurements of mean ion channel open times show that barbiturates act by increasing the proportion of channels opening to the longest open state (i.e., 9 msec), resulting in an overall increase in CL flux into the neuron. 

Figure 4.12 The GABA-A channel functions as a receptor for many multiple different drug classes, including benzodiazepines (e.g., diazepam) and barbiturates (e.g., phenobarbital). There is also a steroid-binding site on the GABA-A channel which may be useful in the future design of general anesthetics.

---