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Interactions Between the Oxytocin and Β2

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Interactions Between the Oxytocin and Β2 INTERACTIONS BETWEEN THE OXYTOCIN AND 2-ADRENERGIC RECEPTORS IN A HUMAN MYOMETRIAL CELL LINE: FUNCTIONAL AND PHYSICAL ANALYSIS By PAULINA K. WRZAL Department of Pharmacology and Therapeutics McGill University November 2011 A thesis submitted to the Faculty of Graduate Studies and Research of McGill University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Copyright Paulina K. Wrzal, 2011 i ABSTRACT The human myometrium is endowed with a vast array of receptors that transmit messages encoded in the external stimuli to the interior of the cell. These include the oxytocin receptor (OTR) and the 2-adrenergic receptor (2AR), mediating uterine contractions and relaxation, respectively. These two receptors belong to the superfamily of G protein-coupled receptors (GPCRs) and are important pharmacological targets because OTR antagonists and 2AR agonists are used to control pre-term uterine contractions. Although they have opposing effects on the myometrium, both receptors activate the MAP kinases ERK1/2, which have been implicated in uterine contractions and the onset of labour. However, the precise mechanisms by which the OTR and the 2AR activate ERK1/2 in a human myometrial cells remains to be characterized. Further, crosstalk between the 2AR and OTR signalling has been shown in the myometrium, but it is unclear what mechanisms underlie such crosstalk. In the present study, we describe a novel molecular mechanism for 2AR-mediated ERK1/2 activation in the human myometrial hTERT- C3 cell line, which involves the activation of a pathway involving Gi-PI3kinase-PKC and Src. We further show that this signalling cascade is dependent on the presence of the OTR. We also demonstrate physical interactions between OTR and 2AR using co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and protein-fragment complementation (PCA) assays in HEK 293 cells. In the context of a receptor heterodimer, these interactions allow for allosteric control of one receptor partner by the other, shown here on the example of ERK1/2 activation in the hTERT-C3 cell line. This study illustrates the notion that formation of GPCR heterodimers can generate receptors with unique properties distinct from individual receptors. Understanding how dimerization is arranged and controlled and more importantly the resulting signalling and pharmacology of such complexes will be crucial for future drug design. ii RÉSUMÉ Les cellules du myomètre humain expriment une vaste gamme de récepteurs transmettant un signal amorcé par des stimuli externes à l’intérieur des cellules. Parmi ces récepteurs, certains jouent un role important dans la contraction utérine, entre autre les récepteurs 2-adrénergiques (2AR) et les récepteurs de l'oxytocine (OTR). Ces deux récepteurs qui appartiennent à la famille des récepteurs à sept domaines transmembranaires couplés aux protéines G (RCPG), représentent des cibles pharmacologiques potentielles. Ceci est essentiellement basé sur le fait que des antagonistes d’OTR et des agonistes du 2AR sont couramment utilisés pour réduire les contractions utérines en cas de risque d'accouchement prématuré. Malgré leurs effets opposés sur le myomètre, ces deux récepteurs activent les MAP kinases ERK1 et ERK2 qui jouent un rôle dans les contractions utérines. Les mécanismes exacts par lesquels ces deux récepteurs activent les MAP kinases demeurent mal définis. De plus, malgré le fait que des interactions entre les signaux mediés par les 2AR et ceux initiés par les OTR ont été démontrés dans les cellules du myomètre, les mécanismes de ces interactions demeurent méconnus. La présente étude décrit un nouveau mécanisme d’interaction et explore une nouvelle voie de signalisation par laquelle les 2AR activent la voie des MAP kinases ERK1/2 dans les lignée cellulaire hTERT-C3 du myomètre et impliquent une voie de signalisation Gi-PI3kinase-PKC et Src. De plus, nous démontrons que cette voie de signalisation nécessite la présence du OTR. Nous démontrons également une interaction physique entre l'OTR et les 2AR dans les cellules HEK 293 par co- immunoprecipitation, essai de complémentation protéine-fragment (PCA) et grace à la technique de transfert d'énergie de résonance de bioluminescence (BRET). L’interaction entre l’OTR et le 2AR, dans un contexte de récepteur hétérodimère, permet le control allostérique de l’activation de ERK1/2 dans les lignée cellulaire hTERT-C3. Cette étude illustre l'idée que la formation iii d'hétérodimères de RCPG pourrait générer des récepteurs ayant des propriétés uniques et distinctes des récepteurs individuels. La compréhension des mécanismes de contrôle de la dimérisation, et du rôle que ceux-ci pourrait jouer dans la signalisation cellulaire, sera important pour le développement des médicaments futurs. iv AKNOWLEDGEMENTS First and foremost I wish to thank my supervisors, Drs. Terry Hébert and Hans Zingg, for their patience, guidance and constant support. Not only are they outstanding scientists but they are also truly remarkable individuals and I am grateful to them for giving me the opportunity to challenge myself and develop as a student/scientist under their watchful eye. I am very thankful for the time they have dedicated to this project and the refining of this thesis. I would also like to thank my graduate committe members Drs. Daniel Bernard, Stéphane Laporte, Greg Miller and my academic advisor Dr. Derek Bowie for their helpful discussions and guidance throughout my studies. I am thankful to all the past and present members of the research team for their encouragement, support, and technical advice, but most importantly for their friendship. I am particularly grateful to all my collaborators, whose names appear on my manuscripts, for their contributions. I would like to extend a special word of gratitude to Dr. Dominic Devost for many valuable discussions as well as technical assistance and advice. Much appreciation goes to Dr. Ahmed Bettaieb for his help in the translation of my abstract. Finally, I extend my most sincere thanks to my parents, Grażyna and Włodzimierz Wrzal, for being the image of perseverance; to my husband, Patrik Balek, for teaching me the true meaning of dedication; to my sisters, Marta and Barbara for their love and laughter which make all things possible; and to my friends for their support. v DEDICATION To Grażyna and Włodzimierz Wrzal & Halina and Stefan Chruściel vi CONTRIBUTIONS OF THE AUTHORS This thesis is assembled in accordance with the regulations of the Faculty of Graduate Studies and Research, McGill University. It is written in a manuscript-based format, containing two original articles co-authored by myself and others. These articles have been arranged as Chapters 2 and 3 in the same sequence as the experimental work that was conducted. The contribution of each author is as follows: Chapter 2: Wrzal, P.K., Goupil, E., Laporte, S.A., Hébert, T.E., and Zingg, H.H. Functional interactions between OTR and 2AR: implications for ERK1/2 activation in human myometrial cells. Cellular Signalling. January 2012;24(1):333-341. The candidate was responsible for most of the experimental work in the manuscript, including conceptualization and design of experiments, and rendering of the first draft of the manuscript. E. Goupil performed the confocal imaging experiments using the Zeiss LSM-510 Meta confocal microscope in the lab of S.A. Laporte. H.H. Zingg and T.E. Hébert supervised the project, participated in the design of experiments and wrote and edited different versions of the manuscript. Chapter 3: Wrzal, P.K., Devost, D., Pétrin, D., Goupil, E., Iorio-Morin, C., Laporte, S.A., Zingg, H.H., and Hébert, T.E. Allosteric interactions between OTR and 2AR modulate ERK1/2 activation in human myometrial cells. Cellular Signalling. January 2012;24(1):342-350. The candidate was responsible for most of the work in the manuscript, including rendering the first draft of the manuscript. D. Devost and C. Iorio-Morin performed the BRET experiments. D. Pétrin performed the PCA experiments. E. Goupil performed the confocal imaging experiments using the Zeiss LSM-510 Meta confocal microscope in the lab of S.A. Laporte. H.H. Zingg and T.E. Hébert supervised the project, participated in the design of experiments and wrote and edited different versions of the manuscript. vii TABLE OF CONTENTS ABSTRACT ..................................................................................................................................... i RÉSUMÉ ........................................................................................................................................ ii AKNOWLEDGEMENTS.............................................................................................................. iv DEDICATION .................................................................................................................................v CONTRIBUTION OF AUTHORS................................................................................................ vi TABLE OF CONTENTS .............................................................................................................. vii LIST OF ABBREVIATIONS ..........................................................................................................x LIST OF FIGURES ...................................................................................................................... xii CHAPTER 1 – INTRODUCTION AND LITERATURE OVERVIEW Overview .........................................................................................................................................1
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