Evaluation of site-selective drug effects on GABA receptors using nanovesicle-carbon nanotube hybrid devices

Site-selective drug effects on the ion-channel activities of gamma-aminobutyric acid type A (GABA(A)) receptors are evaluated by using a nanovesicle-carbon nanotube hybrid device. Here, nanovesicles containing GABAA receptors are immobilized on the channel region of a carbon nanotube field-effect transistor. The receptor responses of this hybrid device to GABA are detected with a high sensitivity down to -1 aM even in the presence of other neurotransmitters. Further, sensitivity differences between two GABA(A)-receptor-subunit compositions of alpha 5 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 are assessed by normalizing the dose-dependent responses obtained from these hybrid devices. Specifically, the GABA concentration that produces 50% of maximal response (EC50) is obtained as -10 pM for alpha 5 beta 2 gamma 2 subunits and-1 nM for alpha 1 beta 2 gamma 2 subunits of GABA(A) receptor. Significantly, the potency profiles of both antagonist and agonist of GABA(A) receptor can be evaluated by analyzing EC50 values in the presence and absence of those drugs. A competitive antagonist increases the EC50 value of GABA by binding to the same site as GABA, while an allosteric agonist reduces it by binding to a different site. These results indicate that this hybrid device can be a powerful tool for the evaluation of candidate drug substances modulating GABA-mediated neurotransmission.

Automated summary

This study evaluates the site-selective drug effects on the ion-channel activities of GABA(A) receptors using a nanovesicle-carbon nanotube hybrid device, achieving high sensitivity in detecting GABA receptor responses and assessing sensitivity differences between different GABA(A) receptor subunit compositions. The results indicate that this hybrid device is a powerful tool for evaluating candidate drug substances modulating GABA-mediated neurotransmission.