PubMed 21248110

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kv10.1

Title: The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs.

Authors: Joachim Ramerstorfer, Roman Furtmüller, Isabella Sarto-Jackson, Zdravko Varagic, Werner Sieghart, Margot Ernst

Journal, date & volume: J. Neurosci., 2011 Jan 19 , 31, 870-7

PubMed link:

GABA(A) receptors mediate the action of many clinically important drugs interacting with different binding sites. For some potential binding sites, no interacting drugs have yet been identified. Here, we established a steric hindrance procedure for the identification of drugs acting at the extracellular α1+β3- interface, which is homologous to the benzodiazepine binding site at the α1+γ2- interface. On screening of >100 benzodiazepine site ligands, the anxiolytic pyrazoloquinoline 2-p-methoxyphenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895) was able to enhance GABA-induced currents at α1β3 receptors from rat. CGS 9895 acts as an antagonist at the benzodiazepine binding site at nanomolar concentrations, but enhances GABA-induced currents via a different site present at α1β3γ2 and α1β3 receptors. By mutating pocket-forming amino acid residues at the α1+ and the β3- side to cysteines, we demonstrated that covalent labeling of these cysteines by the methanethiosulfonate ethylamine reagent MTSEA-biotin was able to inhibit the effect of CGS 9895. The inhibition was not caused by a general inactivation of GABA(A) receptors, because the GABA-enhancing effect of ROD 188 or the steroid α-tetrahydrodeoxycorticosterone was not influenced by MTSEA-biotin. Other experiments indicated that the CGS 9895 effect was dependent on the α and β subunit types forming the interface. CGS 9895 thus represents the first prototype of drugs mediating benzodiazepine-like modulatory effects via the α+β- interface of GABA(A) receptors. Since such binding sites are present at αβ, αβγ, and αβδ receptors, such drugs will have a much broader action than benzodiazepines and might become clinical important for the treatment of epilepsy.