Steady-State Activation and Modulation of the Concatemeric α1β2γ2L GABAA Receptor

The two-state coagonist model has been successfully used to analyze and predict peak current responses of the gamma-aminobutyric acid type A (GABA(A)) receptor. The goal of the present study was to provide a model-based description of GABA(A) receptor activity under steady-state conditions after desensitization has occurred. We describe the derivation and properties of the cyclic three-state resting-active-desensitized (RAD) model. The relationship of the model to receptor behavior was tested using concatemeric alpha 1 beta 2 gamma 2 GABA(A) receptors expressed in Xenopus oocytes. The receptors were activated by the orthosteric agonists GABA or beta-alanine, the allosteric agonist propofol, or combinations of GABA, propofol, pentobarbital, and the steroid allopregnanolone, and the observed steady-state responses were compared with those predicted by the model. A modified RAD model was employed to analyze and describe the actions on steady-state current of the inhibitory steroid pregnenolone sulfate. The findings indicate that the steady-state activity in the presence of multiple active agents that interact with distinct binding sites follows standard energetic additivity. The derived equations enable prediction of peak and steady-state activity in the presence of orthosteric and allosteric agonists, and the inhibitory steroid pregnenolone sulfate. SIGNIFICANCE STATEMENT The study describes derivation and properties of a three-state resting-active-desensitized model. The model and associated equations can be used to analyze and predict peak and steady-state activity in the presence of one or more active agents.