Multiple effects of KCNQ1 activators on the delayed cardiac rectifier potassium channel molecular complex
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Chan, Magnus
issued: 2025-05-02T13:37:35Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: The cardiac delayed rectifier potassium current, IKs, formed by the co-assembly of KCNQ1 and KCNE1 subunits, plays a critical role in cardiac repolarization, acting as a reserve to adapt to higher heart rates and compensating when other repolarization currents are impaired, thereby preventing arrhythmias. Loss of function mutations in these subunits impair cardiac repolarization and are associated with inherited long QT syndrome, increasing the risk of developing a polymorphic ventricular tachycardia known as Torsades de Pointes, which can result in syncope and sudden death. Therapeutic interventions targeting the IKs channel directly to reverse the malignant effects of long QT syndrome hold significant potential but have historically been challenging due to the previously unknown binding sites for IKs activators. In this thesis, I delved into the binding mechanisms of two well-known IKs activators, mefenamic acid and 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), and successfully elucidated their binding sites using electrophysiological and structural biology techniques. These activators potentiate the IKs current by inducing and stabilizing a conformational change in an otherwise hidden binding pocket within the S1/KCNE1/pore complex, slowing channel deactivation. Furthermore, I uncovered a dual mechanism of action for mefenamic acid on the IKs channel. At high concentrations (300 µM), mefenamic acid inhibits wild-type IKs current amplitude while preserving the delay in channel deactivation. Moreover, KCNE1 and KCNQ1 mutations in the previously elucidated binding pocket unmasked the inhibitory actions at lower drug concentrations. I propose that a lower affinity, secondary binding site near the primary binding site is responsible for inhibition, and specific mutations reveal the site. Finally, I demonstrated the graded stoichiometric effects of mefenamic acid on the wild-type IKs channel complex. The K41C mutation in KCNE1, which disrupts the primary bin…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/90959
note: MULTIPLE EFFECTS OF KCNQ1 ACTIVATORS ON THE DELAYED CARDIAC RECTIFIER POTASSIUM CHANNEL MOLECULAR COMPLEX by Magnus Chan B.Sc., The University of British Columbia, 2021 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2025 © Magnus Chan, 2025 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Multiple Effects of KCNQ1 Activators On The Delayed Cardiac Rectifier Potassium Channel Molecular Complex submitted by Magnus Chan in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Dr. David Fedida, Professor, Department of Anesthesiology, Pharmacology & Therapeutics, UBC Supervisor Dr. Michael J. A. Walker, Emeritus Professor, Department of Anesthesiology, Pharmacology & Therapeutics, UBC Supervisory Committee Member Dr. Eric Accili, Associate Professor, Department of Cellular & Physiological Sciences, UBC Supervisory Committee Member Dr. Ismail Laher, Professor, Department of Anesthesiology, Pharmacology & Therapeutics, UBC University Examiner Dr. Edwin Moore, Professor, Department of Cellular & Physiological Sciences, UBC University Examiner iii Abstract The cardiac delayed rectifier potassium current, IKs, formed by the co-assembly of KCNQ1 and KCNE1 subunits, plays a critical role in cardiac repolarization, acting as a reserve to adapt to higher heart rates and compensating when other repolarization currents are impaired, thereby preventing arrhythmias. Loss of function mutations in these subunits impair cardiac repolarization and are associated with inherited long QT syndrome, increasing the risk of developing a polymorphic ventricular tachycardia known as Torsades de Pointes, which can result in syncope …
has type: Thesis/Dissertation
date issued: 2025-11
is shown at: 10.14288/1.0448712
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Fedida, David
type: Text
identifier URI: http://hdl.handle.net/2429/90959