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Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol by Alejandro Tienzo Colozo a Thesis Submitted in Conformity

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Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol by Alejandro Tienzo Colozo a Thesis Submitted in Conformity Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol by Alejandro Tienzo Colozo A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Pharmaceutical Sciences University of Toronto © Copyright by Alejandro Tienzo Colozo, 2009 Modulation of the M2 Muscarinic Cholinergic Receptor by Cholesterol Doctor of Philosophy, 2009 Alejandro Tienzo Colozo Department of Pharmaceutical Sciences, University of Toronto ABSTRACT M2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemmal membranes. Whereas the latter has been shown to exhibit non-competitive effects in the binding of N-methylscopolamine (NMS) and quinuclidinylbenzilate (QNB), which can be explained in terms of cooperativity within a receptor that is at least tetravalent, binding to the former is essentially competitive. Levels of cholesterol in Sf9 membranes were only 5% of those in sarcolemmal membranes and were increased to about 100% by means of cholesterol-methyl-β- cyclodextrin. M2 receptors extracted from CHL-treated Sf9 membranes resembled those from heart; that is, cholesterol induced a pronounced heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were marked discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites, apparently within an oligomer. Cholesterol also was found to increase the affinity of the receptor for NMS and QNB, and the effect was examined for its possible relationship to the known interconversion of cardiac muscarinic receptors between an agonist-specific (R*) and an antagonist-specific (R) state. Cholesterol and N-ethylmaleimide (NEM) were compared for their effect on the affinity of NMS, QNB and four muscarinic agonists, and the data were assessed in terms of an explicit mechanistic model for a receptor that interconverts spontaneously between two states (i.e., R º R*). The data can be described equally well ii by an effect of cholesterol on either the distribution of receptors between R and R* or the affinity of all ligands for both states, with an accompanying effect of NEM on either the affinity or the distribution between states, respectively. Since NEM is known from other data to favor R* over R, cholesterol appears to increase affinity per se. Cholesterol therefore is a determinant of affinity and cooperativity in the binding of orthosteric ligands to the M2 receptor. Both effects are observed in solution and therefore appear to arise from a direct interaction between the lipid and the receptor. iii I never think of the future – it comes soon enough. Albert Einstein iv ACKNOWLEDGEMENTS I thank my father and mother, Wilfredo and Adelina Colozo for their unwavering support in all of my endeavors and I thank them for always trying to instill in me the value of hardwork and education. I am grateful for all the help of those whom I have worked with during my time here, Chi Sum, Paul Park, Amy Ma, Luca Pisterzi, Dar’ya Redka, Rabindra Shivnaraine, David Greiss, Judy Chou and John Dong. I thank my advisory committee members, Dr. Christine Bear, Dr. Hubert Van Tol and Dr. Christopher Yip for their guidance and helpful insights throughout the completion of this work. I am grateful to my supervisor James W. Wells for always making time and to whom I am very much indebted. This work was supported by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Ontario (HSFO), Ontario Graduate Scholarships (OGS) and an Ontario Graduate Scholarship in Science and Technology (OGSST). v TABLE OF CONTENTS ABSTRACT ....................................................................................................................................... ii ACKNOWLEDGEMENTS .................................................................................................................... v LIST OF SCHEMES .......................................................................................................................... vii LIST OF TABLES .............................................................................................................................. ix LIST OF FIGURES.............................................................................................................................. x SUMMARY OF ABBREVIATIONS ..................................................................................................... xii CHAPTER 1: GENERAL INTRODUCTION ....................................................................................... 1 1.1 The Receptor Concept.......................................................................................................... 2 1.2 The G protein-Coupled Receptor Superfamily .................................................................. 11 1.3 Mechanism of Signaling .................................................................................................... 16 1.4 Oligomers of G protein-coupled receptors......................................................................... 29 1.5 Cholesterol ......................................................................................................................... 32 1.6 An Outline of the Thesis .................................................................................................... 39 CHAPTER 2: CHOLESTEROL AS A DETERMINANT OF COOPERATIVITY IN THE M2 MUSCARINIC CHOLINERGIC RECEPTOR ...................................................................................... 43 2.1 Abstract .............................................................................................................................. 44 2.2 Introduction........................................................................................................................ 45 2.3 Materials and Methods....................................................................................................... 47 2.4 Results................................................................................................................................ 56 2.5 Discussion .......................................................................................................................... 63 2.6 Appendix............................................................................................................................ 72 2.7 Acknowledgements............................................................................................................ 74 CHAPTER 3: EFFECT OF CHOLESTEROL ON THE BINDING OF ANTAGONISTS TO THE MUSCARINIC CHOLINERGIC RECEPTOR EXTRACTED FROM PORCINE ATRIA... 89 3.1 Abstract .............................................................................................................................. 90 3.2 Introduction........................................................................................................................ 91 3.3 Materials and Methods....................................................................................................... 92 3.4 Results................................................................................................................................ 98 3.5 Discussion ........................................................................................................................ 100 3.6 Acknowledgements.......................................................................................................... 102 CHAPTER 4: MECHANISTIC BASIS FOR THE EFFECT OF CHOLESTEROL ON THE AFFINITY OF AGONISTS AND ANTAGONISTS FOR THE M2 MUSCARINIC CHOLINERGIC RECEPTOR ......................................................................................................... 108 4.1 Abstract ............................................................................................................................ 109 4.2 Introduction...................................................................................................................... 110 4.3 Materials and Methods..................................................................................................... 113 4.4 Results.............................................................................................................................. 119 4.5 Discussion ........................................................................................................................ 125 4.6 Acknowledgements.......................................................................................................... 131 CHAPTER 5: GENERAL DISCUSSION ........................................................................................ 142 5.1 Insights from the Thesis................................................................................................... 143 5.2 Cooperativity.................................................................................................................... 145 5.3 Functional Role of Cholesterol ........................................................................................ 149 CHAPTER 6: FUTURE DIRECTIONS........................................................................................... 156 6.1 Specificity in the Effects of Cholesterol on Cooperativity and Affinity.......................... 157 6.2 Oligomeric Status of the Receptor ..................................................................................
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