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 γ-aminobutyric acid type A (GABA_A) receptors are evaluated by using a nanovesicle-carbon nanotube hybrid device. Here, nanovesicles containing GABA_A 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 α5β2γ2 and α1β2γ2 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 α5β2γ2 subunits and ∼1 nM for α1β2γ2 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.