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Gating and pore block of the human ether-à-go-go related gene (hERG) voltage-gated potassium channel (Kv11.1)

University of British Columbia

Ion channels are integral membrane proteins that form an aqueous pore through the cell lipid bilayer, and allow ions to traverse the membrane at rates approaching limits set by diffusion. Selectivity and gating differences amongst members of this protein family enable complex physiological processes such as action potentials. The diversity in ion channel selectivity and gating is endowed through structural permutations of protein structure that slightly alter factors such as the rate at which a channel activates or the width of the pore region and thus the type of ions it interacts with. This thesis investigates structural bases for the anomalous gating and drug interaction behaviour exhibited by the human ether-à-go-go related gene (hERG) voltage-gated potassium channel (VGKC). The unique gating kinetics of hERG allow it to fulfill its role as the rapid delayed rectifier potassium current of the cardiac action potential and the unique susceptibility to drug block can compromise this function. Chapter 2 describes how slow deactivation of hERG can be largely attributed to cytosolic domain interaction with channel gating, an interaction that serves to establish a mode shift of the channel gating charge, shifting the deactivation gating pathway to more hyperpolarized potentials. Chapter 3 demonstrates that an interaction between an acidic residue at the bottom of the S1 and a basic residue at the bottom of the S4 stabilizes the closed state of the channel and slows activation. Through gating currents and fluorescence experiments, we propose a model of hERG gating in which this unique interaction stabilizes an early closed state of the channel. Chapter 4 investigates the role of cation-π interactions in hERG drug block, testing the importance of the two most significant residues for drug interaction, Y652 and F656. Using unnatural amino acid mutagenesis, this final study shows that cation-π interactions do not appear to play a major role in drug interaction with the hERG pore.

Text

2017-06-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62066

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/