Kinetic Model of Adsorption of Aqueous Solutes onto Lipid Bilayers: Modulation of the Activity of Membrane Proteins.

Abstract

It has been argued that membrane proteins that are activated by agonist binding and whose activity depends on conformational transitions are sensitive to membrane adsorption of agonists as well as other solutes such as anesthetics. Ligand-gated ion channels such as GABAAR have been observed electrophysiologically to exhibit remarkable temporal complexity, with multiple time scales of desensitization and deactivation that depend on concentration over a very broad range. Earlier theoretical work was able to predict much of this complexity for GABAAR using a model that incorporates a simple Langmuir approximation of adsorption and desorption of neurotransmitters and solutes such as anesthetics, along with classical modeling of ligand binding and conformational transitions among the three canonical protein states. Here, a simple kinetic model is developed that improves on the Langmuir approach by incorporating the energetics of adsorbate-adsorbate (and adsorbate-bilayer) interactions. Predicted equilibrium isotherms are compared to experimental results, along with the time-course of adsorption/desorption, over a range of values of energetic parameters. Initial predictions of effects of adsorbate energetics on ion current traces involving long and short pulses of agonists show remarkably large effects on the time scale(s) of desensitization and deactivation.