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Permanent link (DOI): https://doi.org/10.7939/R37M0455J

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Novel Roles of Plasma Membrane KATP Channels in the Heart Open Access

Descriptions

Other title
Subject/Keyword
KATP, heart, metabolism, channels, AMPK, sulfonylureas, diazoxide, cardiac function
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Youssef, Nermeen Hosny Ibrahim
Supervisor and department
Light, Peter (Pharmacology)
Examining committee member and department
Dyck, Jason (Pediatrics/Pharmacology)
Rodrigues, Brian (Pharmacology)
Yue, Jessica (Physiology)
Seubert, John (Pharmacology)
Light, Peter (Pharmacology)
Department
Department of Pharmacology
Specialization

Date accepted
2015-09-23T13:31:01Z
Graduation date
2015-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Plasma membrane ATP-sensitive potassium (KATP) channels are found in many excitable cell types where they couple cellular metabolism and membrane excitability. . Studies on KATP deficient mice show that parameters of cardiac mechanical function are similar to those of wild-type mice under basal aerobic conditions. However, in the setting of ischemia-reperfusion injury hearts of mice lacking KATP channels were shown to recover poorly after the insult and exhibit larger infarct sizes than in wild-type mice. Absence of KATP channels was also shown to abolish the protective effects of ischemic and pharmacological preconditioning against ischemia-reperfusion injury. Recent evidence suggests that genetic ablation of the channel causes changes in global metabolism. Furthermore, a previous proteomic study has shown that genetic ablation of the KATP channels is associated with a noticeable change in cardiac metabolic proteins. In that regard, efficient energy utilization is one of the means by which the heart can recover functionally after ischemia. Therefore, if cardiac metabolism is suboptimal under basal aerobic conditions, it is likely that the heart becomes more susceptible to damage if subjected to an ischemic insult. In this thesis, the author investigates whether KATP channels regulate cardiac metabolism. If so, how would those changes in metabolic profile contribute to the pronounced cardiac damage observed during ischemia in KATP-deficient mice? In this regard, KATP channels were shown to possess Mg-ATPase activity in addition to their well-identified electrical activity. This Mg-ATPase activity allows the channel to alter the nucleotide concentration in its microenvironment which directly affects channel activity. Therefore, we sought to study the molecular determinants that regulate this enzymatic property. It is plausible that commonly used pharmacological agents that target KATP channels such as diazoxide and sulfonylureas may not only be affecting KATP electrical activity but Mg-ATPase activity as well. The functional consequences of these effects are unknown thus far, however, elucidation of these effects provides insight into the manifestation of side effects that may occur due to the use of such pharmacological agents. Due to the close association between KATP channels and several nucleotide-sensitive enzymes known to modulate metabolism, most notably AMP-activated protein kinase (AMPK), we investigated whether KATP channel openers and inhibitors affected activity of this enzyme. We also examined the effect of diazoxide, glibenclamide and gliclazide on Mg-ATPase activity of the channel in an effort to correlate the enzymatic activity of the channel and activity of AMPK. Overall, the findings in this thesis highlight the importance of the presence of an intact plasma membrane KATP channel metabolome in the regulation of cardiac metabolism via modulation of AMPK activity. Moreover, we show that alteration of Mg-ATPase activity can directly affect pharmacological sensitivity of KATP channels to drugs that are designed to modulate their electrical activity. Understanding the functional consequences of the alteration of non-electrical properties of KATP channels provides clues to aid the development of more specific pharmacological agents with less prominent adverse effects.
Language
English
DOI
doi:10.7939/R37M0455J
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
The molecular genetics of sulfonylurea receptors in the pathogenesis and treatment of insulin secretory disorders and type 2 diabetes - Veronica Lang, Nermeen Youssef, Peter E. Light. 2011 Dec;11(6):543-51Molecular determinants of ATP-sensitive potassium channel Mg-ATPase activity and diazoxide sensitivity- Mohammad Fatehi, Chris Carter, Nermeen Youssef, Beth Hunter, Andy Holt, Peter E. Light 2015 Jul 7. pii: BSR20150143"Molecular Defects in Cardiovascular Disease". Editors: Naranjan S. Dhalla, Makoto Nagano,Bohuslav Ostadal, Springer 2011.Pages 17-28 ISBN: 978-1-4419-7129-6"Phosphorylation status of matrix metalloproteinase 2 in myocardial ischaemia–reperfusion injury" Heart Journal 2012;98:656-662 doi:10.1136/heartjnl-2011-301250

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