Benzodiazepines, GABAergic drugs and the GABA-A receptor

Benzodiazepines are GABA agonists, binding indirectly to the GABA-A receptor but not the ligand binding site itself, and GABA binding to the ligand site is still neccessary for ion channel opening. Benzodiazepines bind to an allosteric site on the receptor know as the benzodiazepine binding site. When benzodiazepines are bound to the receptor in the presence of GABA, ion pore opening is enhanced, and therefore allowing greater conductance of Cl- ions through the pore.

The GABA-A receptor is a heteromer consisting of 5 protein subunits (pentamer) in a ring shape around a central pore. All GABA-A receptors contain α and β subunits, with most containing 2α and 2β subunits and 1γ subunit (α₂β₂γ). 6 different α _{subunits, 3}β and ₃γ subunits exist, so there are many possibilities. The GABA binding site is located between alpha and beta subunits, making two per receptor protein, and the benzodiazepine binding site exists between the alpha and gamma subunits, making one available in a common receptor protein. Note: Not all GABA-A receptors have a benzodiazepine site - some do not have gamma subunits, and α4 and α6 subunits are arginine not histine based meaning they cannot functionally bind with benzodiazepines. Binding sites with an α1 subunit  may higher affinity for more sedative benzodiazepines over binding sites with α2 or α3 subunits, which may be associated with drugs with a more anxiolytic effect.