GABAA Rε Inhibitors

Chemical inhibitors of GABAA Rε can be categorized based on their action mechanism and binding sites on the receptor complex. Picrotoxin, for instance, is known to block the chloride channel associated with GABAA Rε, thereby directly inhibiting its ionotropic function. This blockade prevents chloride ions from flowing through the channel, which is essential for the inhibitory effect of the GABAA receptor. Another channel blocker, Penicillin, operates by binding within the channel pore of the GABAA Rε, thus obstructing chloride ion movement and inhibiting receptor function. Similarly, dihydro-beta-erythroidine and Furosemide inhibit the GABAA Rε receptor by blocking the receptor's chloride channel at higher concentrations, which diminishes the receptor's ability to conduct chloride ions, a critical component of its inhibitory action in neuronal signaling.

On the other hand, compounds like Bicuculline and Gabazine act as competitive antagonists at the GABA binding site of GABAA Rε. By occupying this site, they prevent the neurotransmitter GABA from activating the receptor, which is necessary for the receptor's inhibitory action. Flumazenil also binds to a modulatory site on GABAA Rε, specifically the benzodiazepine site, and inhibits the potentiating effects of benzodiazepines on the receptor. Zinc sulfate exerts its inhibitory effect allosterically, by attaching to sites on GABAA Rε that are distinct from the GABA binding site, leading to a reduction in receptor activity. Other chemicals like Strychnine exhibit nonspecific inhibition at high concentrations by diminishing chloride ion conductance, thus affecting the GABAA Rε receptor among others. Secobarbital and Isoflurane, at high concentrations, can promote receptor desensitization-a state in which the receptor becomes less responsive to GABA-thus inhibiting GABAA Rε function. Lastly, Tertiapin indirectly alters neuronal excitability by inhibiting GIRK channels, which can lead to an overall inhibitory effect on neurons that express GABAA Rε receptors.