Molecular Mechanisms of Ion and Solute Interactions with Voltage-Gated Ion Channels

Date
2016
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Ion channels are membrane proteins that catalyze passive and selective ion transport across cellular membranes. They respond to external stimuli such as changes of membrane voltage by opening or closing the channels. Accordingly they play pivotal roles in pace-making, neuronal signaling, smooth muscle function and are major targets of drug development. The present thesis provides a systemic study of the interactions of voltage-gated ion channels with various ions and solutes. It was proposed that prokaryotic voltage-gated sodium (Nav) channels adopt a unique selective strategy to conduct and select Na+ ions, considering the striking structural differences between Nav channels from prokaryotes and eukaryotes. A single favored ion binds tightly to the selectivity filter. Inter-ion interactions within the pore make the fast permeation possible. However, relative permeabilities of organic ions still relate to the binding free energies of a single ion. We also investigated two engineered NaK mutants. The results suggested that coordination number for transport ions alone is an insufficient predictor of site selectivity, while chemical composition (ratio of carbonyls and water molecules) correlates well with preferences for K+. Multi-ion effects such as dependence on the barriers and wells for permeant ion on the type of co-permeant ion were found to play a significant role in the selectivity signature of the channel as well. Many antiarrhythmic agents used for the maintenance of sinus rhythm can block the hERG potassium channel and cause a drug-induced Long QT syndrome. Homology models of hERG were employed to study the blockade mechanisms. This thesis proposed two paths for a heart-rate-lowering agent, ivabradine, accessing the inner cavity of hERG channel and they were validated by the experimental study. Molecular docking and simulations indicate that ivabradine may also access the inner cavity of the hERG via a lipophilic route besides from the open gate. We also observed startling differences for the binding process of an antiarrhythmic agent, dofetilide, in the open and open-inactivated hERG channel. Drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain with higher binding affinities.
Description
Keywords
Biology, Biophysics
Citation
Wang, Y. (2016). Molecular Mechanisms of Ion and Solute Interactions with Voltage-Gated Ion Channels (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26993