GABAA θ Inhibitors

Chemical inhibitors of GABAA θ function through various mechanisms to impede its activity. Bicuculline, for example, competes with GABA for its binding sites on GABAA θ, obstructing the receptor's normal response to the neurotransmitter. This competitive antagonism effectively inhibits the influx of chloride ions that would typically result in neuronal hyperpolarization and inhibition. Similarly, Picrotoxin acts by binding to the chloride channel of the GABAA θ receptor, not to compete with GABA itself, but to obstruct the channel pore, hindering chloride ion flow and receptor function. In contrast, Strychnine non-selectively binds to the receptor, which can inhibit its channel function, even though its primary target is the glycine receptor.

Continuing with the theme of channel blockage, compounds like Tertiapin-Q and TBPS also inhibit GABAA θ indirectly through their action on associated ion channels. Tertiapin-Q blocks GIRKs, which are functionally coupled with GABAA θ, thereby disrupting the downstream signaling that contributes to the receptor's inhibitory effects. TBPS binds allosterically to the chloride channel, locking it in a closed state which inhibits the receptor's function. Zinc, on the other hand, binds to a modulatory site on GABAA θ, altering the receptor's conformation which results in diminished sensitivity to GABA and consequential inhibition. Flumazenil operates through competitive antagonism at the benzodiazepine site on the receptor, inhibiting the effect of benzodiazepines on GABAA θ and thus the receptor's overall function. Alongside, Penicillin non-selectively interacts with the receptor to inhibit its chloride channel function. High concentrations of Ethanol disrupt the membrane environment of GABAA θ, leading to a decrease in receptor sensitivity to GABA, thereby inhibiting receptor function. Ivermectin, although known for enhancing the effects of other antagonists, can at certain concentrations allosterically modify the receptor's response to GABA, resulting in inhibition. Gabazine specifically targets the GABA binding site on GABAA θ, preventing receptor activation through competitive antagonism. Lastly, Cicutoxin impedes the receptor's chloride ion conductivity by blocking the channel linked to GABAA θ, leading to inhibition of the receptor's inhibitory neurotransmission.