Anesthetic Modulation of Signal Transduction Pathways in the α4β2 nAchR Revealed by the Perturbation-Based Markovian Transmission Model

Abstract

The gating mechanism of ligand-gated ion channels and anesthetic modulation of channel gating remain to be determined. In this study, we used the perturbation-based Markovian transmission model to investigate the time-dependent signal propagation in the neuronal nicotinic acetylcholine receptor (α4β2 nAChR) under initial perturbations by agonist binding. Both open- and closed-channel α4β2 nAChR conformations in the presence and absence of the anesthetic halothane, from our previous computational studies, were examined. We found that signal transduction in α4β2 resembles the conformation wave mechanism. In all systems, the perturbation signal flows from the agonist-binding sites up toward the main immunogenic region, then down to the bottom of the beta barrel, followed by the extracellular (EC)/transmembrane (TM) interface, and finally to the transmembrane domain, as measured by the time dependence of the maximum probability flux. The EC domain of the open- and closed-channel α4β2 conformations showed different dynamic responses to the perturbation at the agonist-binding site: many more residues in the EC domain of the open-channel α4β2 nAChR exhibited frequent fluctuation. In the system with halothane, the signal transduction within pre-TM1 (R207), Cys-loop (F137, P138, F139), and TM2-TM3 linker (L271) slowed down in some of the subunits, but speeded up in others. The changes in signal transduction at the EC/TM interface may underlie the effects of anesthetics on the α4β2 nAChR. Supported by NIH (R01GM066358, R01GM056257, R37GM049202).