Application of the Co-Agonist Concerted Transition Model to Analysis of GABAA Receptor Properties

Abstract

The co-agonist concerted transition model is a simple and practical solution to analyze various aspects of GABAA receptor function. Several model-based predictions have been verified experimentally in previous reports. We review here the practical implications of the model and demonstrate how it enables simplification of the experimental procedure and data analysis to characterize the effects of mutations or properties of novel ligands. Specifically, we show that the value of EC50 and the magnitude of current response are directly affected by basal activity, and that coapplication of a background agonist acting at a distinct site or use of a gain-of-function mutation can be employed to enable studies of weak activators or mutated receptors with impaired gating. We also show that the ability of one GABAergic agent to potentiate the activity elicited by another is a computable value that depends on the level of constitutive activity of the ion channel and the ability of each agonist to directly activate the receptor. Significantly, the model accurately accounts for situations where the paired agonists interact with the same site compared to distinct sites on the receptor.

Keywords: GABAA receptor; activation; agonist; ion channel; model; modulation; potentiation; potentiator..