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FUNCTIONAL SELECTIVITY DOWNSTREAM of Gαi/O-COUPLED RECEPTORS Tarsis Brust Fernandes Purdue University

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FUNCTIONAL SELECTIVITY DOWNSTREAM of Gαi/O-COUPLED RECEPTORS Tarsis Brust Fernandes Purdue University Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations January 2015 FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS Tarsis Brust Fernandes Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Recommended Citation Brust Fernandes, Tarsis, "FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS" (2015). Open Access Dissertations. 1448. https://docs.lib.purdue.edu/open_access_dissertations/1448 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Graduate School Form 30 Updated 1/15/2015 PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance This is to certify that the thesis/dissertation prepared By Tarsis Brust Fernandes Entitled FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS For the degree of Doctor of Philosophy Is approved by the final examining committee: Val J. Watts Chair Jean-Christophe Rochet Gregory H. Hockerman Donald F. Ready To the best of my knowledge and as understood by the student in the Thesis/Dissertation Agreement, Publication Delay, and Certification Disclaimer (Graduate School Form 32), this thesis/dissertation adheres to the provisions of Purdue University’s “Policy of Integrity in Research” and the use of copyright material. Val J. Watts Approved by Major Professor(s): Jean-Christophe Rochet 7/13/15 Approved by: Head of the Departmental Graduate Program Date FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS A Dissertation Submitted to the Faculty of Purdue University by Tarsis Brust Fernandes In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2015 Purdue University West Lafayette, Indiana ! ii I dedicate this dissertation to my lovely wife, Isabelle Verona Brust, who has been near me helping and supporting me throughout my graduate studies. I also dedicate this dissertation to my parents, Juares and Ariadne Fernandes, who have always loved me and from whom I still learn extensively about the values of life. Finally, I dedicate this dissertation to my sister, Larissa Brust Fernandes, for her friendship and care. ! iii ACKNOWLEDGEMENTS I wish to thank my mentor, Dr. Val J. Watts, for his sustained support and effort to help me becoming a better scientist and a better person. I will proudly carry his name with me for the rest of my scientific career and his lessons for the rest of my life. I would also like to thank the members of my thesis advisory committee, Dr. Jean-Christophe Rochet, Dr. Gregory Hockerman, and Dr. Donald Ready. I would like to thank the past and current members of the Watts laboratory, Dr. Jason Conley, Elisabeth Garland-Kuntz, Dr. John McCorvy, Dr. Karin Ejendal, Monica Velasquez, and Trevor Doyle, for their friendship, conversations, and help with scientific projects. I would also like to thank the people who collaborated with us in the various scientific projects that I participated during graduate school, especially Dr. David Roman, Michael Hayes, Dr. Kevin Burris, Dr. Richard van Rijn, Doungkamol Alongkronrusmee, Dr. Catherine Hill, Dr. Mingji Dai, and Dr. Yoon Yeo. I would also like to thank my past research advisors, Dr. Fabio Alves, Dr. David William Provance Jr., and Dr. Octavio Fernandes, for their patience and lessons in the beginning of my scientific career. I would also like to thank my many friends who supported me and provided numerous entertaining activities in my free time. In particular, I would like to thank all my soccer friends and also the members of the Purdue Brazilian Jiu Jitsu club, the Purdue Muay Thai club, and Central Presbyterian Church. ! iv Finally, I wish to thank God for everything and my lovely wife Isabelle Verona Brust for her sustained love, care, and support during graduate school. I would also like to thank her for designing the schematic figures in this dissertation. ! v TABLE OF CONTENTS Page ABSTRACT ....................................................................................................................... xi LIST OF PUBLICATIONS ............................................................................................. xiii! CHAPTER 1. INTRODUCTION ........................................................................................1 1.1 G protein-coupled receptors (GPCRs) ...................................................................1 1.1.1 Therapeutic relevance .....................................................................................1 1.1.2 Families of GPCRs .........................................................................................2 1.1.3 Structure of GPCRs ........................................................................................4 1.1.4 Signaling properties of GPCRs .......................................................................6 1.1.4.1 Signaling cycle ................................................................................6 1.1.4.2 Gα subunits ......................................................................................8 1.1.4.3 Gβγ subunits ....................................................................................9 1.1.4.4 β-arrestins ......................................................................................11 1.1.5 Adenylyl cyclases .........................................................................................13 1.1.5.1 Physiological functions of adenylyl cyclases ................................15 1.1.6 Complex signaling pathways ........................................................................19 1.1.6.1 ERK phosphorylation .....................................................................19 1.1.6.2 Heterologous sensitization .............................................................22 ! vi Page 1.1.6.3 Dynamic mass redistribution .........................................................24 1.2 Functional selectivity ...........................................................................................25 1.2.1 History and definition ...................................................................................25 1.2.2 Clinical relevance and examples ...................................................................27 1.2.3 Quantification of functional selectivity ........................................................30 1.2.3.1 Equimolar comparison ...................................................................31 1.2.3.2 Equiactive comparison ...................................................................31 1.2.3.3 The Black and Leff operational model ..........................................32 1.2.3.4 Transduction coefficient ................................................................34 1.2.3.5 Sigma comparison ..........................................................................35 1.3 Dopamine receptors ..............................................................................................36 1.3.1 Dopamine: neuroanatomy and function ........................................................36 1.3.2 Signaling properties and expression patterns of dopamine receptors ...........38 1.3.3 Dysfunctions in the dopaminergic system ....................................................41 1.4 Opioid receptors ...................................................................................................45 1.4.1 Neuroanatomy and function of opioid receptors ..........................................45 1.4.2 Ligands of the µ-opioid receptor as analgesics .............................................48 1.4.2.1 Ligand-directed functional selectivity at the µ-opioid receptor and type 1 adenylyl cyclase ..............................................................................49 CHAPTER 2. NEW FUNCTIONAL ACTIVITY OF ARIPIPRAZOLE REVEALED: ROBUST ANTAGONISM OF D2 DOPAMINE RECEPTOR-STIMULATED Gβγ SIGNALING ......................................................................................................................53 ! vii Page 2.1 Introduction ..........................................................................................................53 2.2 Methods ................................................................................................................55 2.2.1 Compounds used ...........................................................................................55 2.2.2 Cell culture ....................................................................................................56 2.2.3 Gαi/o assay ....................................................................................................56 2.2.4 Gβγ assay ......................................................................................................57 2.2.5 Heterologous sensitization ............................................................................58 2.2.6 Dynamic mass redistribution ........................................................................58 2.2.7 Data collection and analysis ..........................................................................60 2.3 Results ..................................................................................................................60 2.3.1 Aripiprazole is a partial agonist for Gα activation through the DRD2 ........60 2.3.2 Aripiprazole is an antagonist of Gβγ signaling through the DRD2 ..............63 2.3.3 Aripiprazole’s effects on heterologous sensitization ....................................65 2.3.4 Aripiprazole’s
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