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A kinetic model of the effect of agonist and anesthetics on ligand-gated ion channels, developed in earlier work, is further refined and used to predict traces observed in fast-perfusion electrophysiological studies on recombinant GABAA receptors under a wide range of agonist and/or anesthetic concentrations. The model incorporates only three conformational states (resting, open, and desensitized) but allows for the modulation of the conformational free energy landscape connecting these states resulting from adsorption of agonist and/or anesthetic to the bilayer in which the protein is embedded. The model is shown to reproduce the diverse and complex features of experimental traces remarkably well, including both anesthetic-induced and agonist-induced traces, as well as the modulation of agonist-induced traces by anesthetic, either coapplied or continuously present. The solutions to the kinetic equations, which give the time-dependence of each of the nine protein states (three ligation states for each of the three conformations), describe the flow of probability among these states and thus reveal the kinetic underpinnings of the traces. Many of the parameters in the model, such as the desorption rate constants of anesthetic and agonist, are directly related to model-independent experimental measurements and thus can serve as a definitive test of its validity.

The time- and concentration-dependence of agonist-induced ion currents through postsynaptic receptors is often remarkably complex, as is the modulation of these currents by other solutes such as anesthetics. Traditionally, kinetic models have been developed that involve agonist binding and conformational transitions among a manifold of protein conformational states engineered to reproduce the complexity of the electrophysiological results. In the present work, an alternative model is proposed that minimizes the number of conformational states while additionally incorporating effects of adsorption of agonist and nonbinding compounds such as anesthetics to the bilayer in which these intrinsic membrane proteins are embedded. Adsorption of these aqueous solutes alters bilayer physical properties, which in turn can distort the protein conformational free energy landscape, and thus alter the rate constants of protein conformational transitions. The complexity of the predicted ion currents then arises from the time-dependence of solute adsorption, resulting in strongly time-dependent transition rate “constants”. If only nonbinding solutes are present, the model simplifies considerably. Best fits with respect to a small set of parameters of the predicted current traces are found to be in excellent agreement with previously measured currents in GABAA receptors induced by a broad range of supraclinical concentrations of isoflurane and sevoflurane.