Biased Allosteric Regulation of the Prostaglandin F2α Receptor: From

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Biased Allosteric Regulation of the Prostaglandin F2α Receptor: From Biased Allosteric Regulation of the Prostaglandin F2 Receptor: From Small Molecules to Large Receptor Complexes By Eugénie Goupil Department of Pharmacology and Therapeutics McGill University, Montréal, Canada November, 2012 A thesis submitted to McGill in partial fulfillment of the requirements of the degree of Doctor of philosophy Copyright ©Eugénie Goupil, 2012 ''In theory, there is no difference between theory and practice. In practice, there is.'' -Lawrence Peter ''Yogi'' Berra ii Abstract G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors, and thus some of the most important targets for drug discovery. By binding to the orthosteric site where endogenous ligands bind, agonists and antagonists differentially modulate signals sent downstream from these receptors. New evidence suggests that GPCRs possess topographically distinct or allosteric binding sites, which may differentially modulate agonist- and antagonist-mediated responses to selectively affect distinct signalling pathways coupled to the same receptor. These sites may either positively or negatively regulate receptor activity, depending on the pathway in question, and thus can act as biased ligands, leading to functional selectivity (or ligand-directed signalling). Another way of allosterically regulating GPCR signalling is through receptor oligomerization, which has recently emerged as a common mechanism for regulating receptor function. The GPCR for prostaglandin F2 FP, is implicated in many important physiological responses, such as parturition, smooth muscle cell contraction and blood pressure regulation. Therefore, evaluating the potential use of allosteric modulators of FP to fine-tune PGF2-mediated signals, as well as generating a better understanding of its putative oligomerization partners would be of significant pharmacological and clinical interest. iii In this thesis, I studied the impact of modulating, in both heterologous (HEK 293 cells) and homologous (osteoblast, myometrial or vascular smooth muscle cells) systems, downstream cellular responses of FP by 1) an orthosteric, but biased ligand, previously characterized as a neutral antagonist 2) an allosteric molecule, designed based on the extracellular domains of FP, which had biased signalling properties and, 3) heterodimerization with a receptor partner, the angiotensin II type I receptor, where I demonstrated the asymmetrical organization of this new signalling unit both in vitro and in vivo. Overall, my thesis unveils important roles for biased, allosteric ligands and receptor oligomerization in modulating FP signalling. This work also demonstrates the importance of understanding distinct receptor conformations, and their effects on cellular responses, which are adopted when GPCRs are allosterically modulated, to design better therapeutics with improved efficacy profiles and reduced side effects. iv Résumé Les récepteurs couplés aux protéines G (RCPGs) repésentent la plus grande famille des récepteurs exprimés à la membrane plasmique et sont aussi considérés comme étant des cibles imporantes dans la découverte de nouveaux médicaments. Lorsque des agonistes ou antagonistes se lient au site de liaison endogène d’un RCPG, ou site orthostérique, ces derniers peuvent en moduler les signaux déployés en aval. De nouvelles évidences suggèrent que les RCPGs possèdent des sites de liaison topographiquement distincts des sites orthostériques, appelés sites allostériques. Ces sites allostériques sont suspectés de sélectivement réguler les différents sentiers de signalisation induits lorsque les récepteurs sont liés, de manière concomitante, par des agonistes ou antagonites. De plus, ces sites allostériques peuvent réguler de manière positive ou négative les différentes activités d’un RCPG, et donc être considérés comme étant des ligands biasés, menant à ce qui est appelé la sélectivité fonctionnelle (aussi connue sous le nom de signalisation dirigée par le ligand). Une autre façon de réguler les signaux des RCPGs, qui est présentement vue comme un autre mécanisme contrôlant leur fonction, est l’oligomérization de ces derniers avec d’autres RCPGs, phénomène pouvant être aussi considéré comme de l’allostérisme. Le RCPG pour la prostaglandine F2, FP, est impliqué dans plusieur réponses physiologiques d’importance, telles la parturition, la contraction des cellules musculaires lisses, ou même la régulation de la pression sanguine. En somme, l’évaluation des différentes façons par lesquelles les signaux de FP v peuvent être altérés, soit par l’utilisation d’un modulateur allostérique, soit par l’oligomérisation avec d’autres RCPG, est considérée primordiale d’un point de vue clinique et pharmacologique. Dans cette thèse, j’ai étudié les impacts de la modulation des réponses en aval de FP dans des systèmes hétérologues (cellules HEK 293) ou homologues (cellules ostéoblastiques, myométriales ou musculaires lisses vasculaires), lorsque celui-ci était régulé par 1) un ligand orthostérique, mais à fonctions biaisées, connu précédemment comme un antagoniste neutre, 2) une molecule allostérique, inspirée des domaines extracellulaires de FP, étant aussi capable de propriétés de signalisation biaisées et par 3) l’hétérodimérisation de FP avec un autre récepteur- « partenaire », le récepteur à l’angiotensine II, pour lequel j’ai démonté la présence d’une organisation asymétrique de cette nouvelle « unité » de signalisation, in vitro et in vivo. De manière générale, ma thèse soulève le rôle des ligands biaisés ou allostériques, ainsi que de l’oligomérisation, dans la modulation des signaux cellulaies dirigés par FP. Le travail accompli démontre aussi l’importance de comprendre les différentes conformations, et leurs effets sur les réponses cellulaires, prises quand les RCPGs sont modulés, afin de générer de meilleurs médicaments ayant une meilleure efficacité, mais aussi des effets secondaires plus minimes. vi Table of Contents Abstract.................................................................................................................. iii Résumé.................................................................................................................... v Table of Contents.................................................................................................. vii Acknowledgements.............................................................................................. xiii Author Contributions ............................................................................................ xv List of Figures .................................................................................................... xviii List of Tables ..................................................................................................... xxiii Abbreviations..................................................................................................... xxiv CHAPTER 1: General introduction and literature review...................................... 1 1.1 Preface........................................................................................................... 2 1.2 G protein-coupled receptors.......................................................................... 3 1.3 The heterotrimeric G proteins....................................................................... 5 1.3.1 Discovery, structure and mechanism of action ...................................... 5 1.3.2 G subunits and their downstream effectors ......................................... 8 1.3.3 G subunits and their downstream effectors...................................... 11 1.3.4 Receptor tyrosine kinase transactivation by GPCRs............................ 12 1.4 Desensitization and endocytosis of GPCRs................................................ 13 1.5 G protein-independent signalling, the case of -arrestins........................... 16 1.6 The F prostanoid receptor, FP..................................................................... 17 1.6.1 The prostanoids and the physiological roles of PGF2/FP ................. 18 vii 1.6.2 Prostaglandin F2-induced signalling ................................................. 21 1.7 The angiotensin II type I receptor, AT1R................................................... 23 1.7.1 The renin-angiotensin-aldosterone system........................................... 23 1.7.2 Physiological roles of Ang II/AT1R .................................................... 24 1.7.3 Angiotensin II-induced signalling........................................................ 26 1.7.4 Interplay between FP and AT1R systems............................................ 28 1.8 Functional selectivity of GPCR signalling with biased-ligands ................. 29 1.8.1 Historical aspects and conceptual innovations .................................... 29 1.8.2 The true nature of GPCR ligands revealed .......................................... 32 1.8.3 Time dependence of ligand-induced functional selectivity ................. 35 1.9 GPCR functional selectivity with allosteric modulators............................. 37 1.9.1 Modulation of GPCRs by allosteric ligands ........................................ 37 1.9.2 Allosteric modulation of Class C GPCRs............................................ 39 1.9.3 Allosteric modulation of Class A GPCRs............................................ 41 1.9.4 The use of bitopic ligands to achieve functional selectivity ................ 44 1.10 Structural correlates of allosteric and biased signalling............................ 46
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