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The Mechanism of Action of External Protons on Herg Potassium Channels

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The Mechanism of Action of External Protons on Herg Potassium Channels The Mechanism of Action of External Protons on hERG Potassium Channels by Yu Patrick Shi B.Sc., Simon Fraser University, 2011 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Department of Biomedical Physiology and Kinesiology Faculty of Science © Yu Patrick Shi 2018 SIMON FRASER UNIVERSITY Fall 2018 Copyright in this work rests with the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Approval Name: Yu Patrick Shi Degree: Doctor of Philosophy Title: The Mechanism of External Protons on hERG Potassium Channels Examining Committee: Chair: William Cupples Professor Thomas Claydon Senior Supervisor Associate Professor Peter Ruben Supervisor Professor Edgar Young Supervisor Associate Professor Damon Poburko Internal Examiner Associate Professor Gea-Ny Tseng External Examiner Professor Date Defended/Approved: November 19th, 2018 ii Ethics Statement iii Abstract Myocardial ischemia occurs when there is a reduction of blood flow to the heart due to blockage of an artery, causing inefficient delivery of oxygen and nutrients to the heart muscle. Acidosis is one of the major consequences during myocardial ischemia and affects a wide array of ion channels in the heart that may predispose individuals to cardiac arrhythmia. The human ether-à-go-go (hERG) related gene encodes the potassium channel that conducts the IKr current, which is responsible for the repolarization phase of the cardiac action potential and is particularly sensitive to external acidosis. External acidosis had been well observed to reduce hERG channel overall conductance, right-shift the voltage-dependence of activation, and accelerate deactivation rate, all of which lead to a loss-of-function effect on the hERG channels. We hypothesized that this can prolong action potential duration, increase susceptibility of individuals to long QT syndrome and reduce the protective current against premature ectopic beat. My first study aimed to determine the site and mechanism for the right-shift in the voltage-dependence of activation. I found that external protons disrupt stable interactions formed by the cation binding pocket, compose of three acidic residues: D456, D460 in S2, and D509 in S3, with positive charges in S4 to destabilize the activated voltage sensor. My second study aims to determine the site and mechanism for the acceleration of deactivation induced by external protons. Using voltage-clamp fluorimetry and gating current measurement with long duration protocols to measure voltage sensor mode-shift, we determined that external protons reduced the voltage sensor mode-shift by right shifting the voltage-dependence of deactivation suggesting that the relaxed conformation of the voltage sensor is destabilized and that D509 is a critical protonation site. In my last study, I used zebrafish heart as a translational model, with the optical mapping technique to investigate the effect of external protons on the overall cardiac action potential. We discovered that at low pH, the cardiac action potential is significantly prolonged, triangulation is increased, and the electrical restitution curve is flattened, which are all predictors for arrhythmogenicity. Keywords: hERG; pH; Acidosis; Relaxation; Zebrafish; optical mapping; iv Dedication To My Family and Grandmother. v Acknowledgements My PhD journey was a roller coaster ride of a lifetime that I never regretted getting on. Despite the ups and downs, this was an unforgettable experience. A lot of this was because of all the people who have crossed path and helped me along the way. I would like to thank them and show my appreciation. I want to first show my appreciation and gratitude to my senior supervisor, Dr. Tom Claydon, for all his dedicated supervision, and guidance. Without his trust in me during my undergraduate co-op term with him, I would have never had the opportunity to partake on this journey. The support, and encouragement I received from him during my PhD was extremely motivating and is a big factor that drive my passion for scientific research. He always encourages and challenge students and from this, I have developed and grown under his leadership to be more well-rounded person. Here, I would also like to thank Dr. Peter Ruben, and Dr. Edgar Young, on my supervisory committee, for their insightful comments, and advices to help me become a better thinker. Next, I would like to thank all my previous and current lab members from the Claydon lab. Many have come and gone whom have greatly impacted my life. Dr. Yen May Cheng have really taught me what it is to do research the right way, her meticulous attention to detail and organization is contagious and inspiring. A big thank you to Dr. Samrat Thouta and Danielle Jeong for the countless scientific discussions and afterhours heartfelt talks. Ji Qi, whom was a technician and a lab “mom”, for making all the DNA and RNA for us, taking care of us, and giving life advices. Christina Hull, whom can lighten up any conversation, make the lab environment fun, but also contribute to great scientific discussion as well. I cannot thank the members from Dr. Glen Tibbits lab and Dr. Glen Tibbits enough for their patient guidance in teaching me how to operate the optical mapping system. Dr. Glen Tibbits for his fatherly support and graciously included me as one of his own lab member. Dr. Eric Lin for the wealth of support on the optical mapping rig, and his patience with me when troubleshooting the rig. Huge thanks to Sanam Shafaattalab, Marvin Gunawan, Alison Li, Sabi Sangha, Kaveh Rayani, Barun Kim for their friendship and support over the years, and all the past and present friends and colleagues of the Molecular Cardiac Physiology Group (MCPG) and BPK department. vi Lastly, I would like to thank my parents, and Grace Song for being on this ride with me all these years. They have shared my frustration and celebrated my success, unconditionally, and I can never have completed this journey without their support. Finally, I would like to thank my grandmother, who passed away from cancer, for inspiring and motivating me to walk the path of scientific research. vii Table of Contents Approval .......................................................................................................................... ii Ethics Statement ............................................................................................................ iii Abstract .......................................................................................................................... iv Dedication ....................................................................................................................... v Acknowledgements ........................................................................................................ vi Table of Contents .......................................................................................................... viii List of Tables ................................................................................................................. xii List of Figures................................................................................................................ xiii List of Acronyms ........................................................................................................... xiv Glossary ....................................................................................................................... xvii Chapter 1. Introduction .............................................................................................. 1 + 1.1 Voltage-gated K channel diversity ....................................................................... 1 1.2 HERG potassium channels ................................................................................... 3 1.2.1 Physiological role of hERG channels ............................................................. 3 1.2.2 Features of the hERG channel architecture ................................................... 9 1.2.3 Unique hERG channel gating ...................................................................... 14 1.2.3.1 Molecular basis of hERG activation ...................................................... 16 1.2.3.2 Molecular basis of hERG inactivation ................................................... 17 1.2.3.3 Molecular basis of hERG deactivation .................................................. 19 1.2.3.4 Molecular basis of hERG mode-shift ..................................................... 20 1.3 Myocardial ischemia ........................................................................................... 21 1.3.1 Background ................................................................................................. 22 1.3.2 Major ion concentration changes during myocardial ischemia ..................... 23 + 1.3.2.1 Increase in [K ]o .................................................................................... 23 + 1.3.2.2 Accumulation of [Na ]i ........................................................................... 24 2+ 1.3.2.3 Changes in [Ca ]i distribution ............................................................... 25 1.3.2.4 Changes to extracellular and intracellular [H+ ] ...................................... 26 1.4 Effect of acidosis on major ion channels ............................................................. 27 1.5 Effects of external acidosis on hERG channels ..................................................
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