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Functional Characterization of the 5-Oxo-ETE Receptor OXE-R and Identification of the First Small Molecule Antagonist with a Novel Mechanism of Ligand Bias

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Functional Characterization of the 5-Oxo-ETE Receptor OXE-R and Identification of the First Small Molecule Antagonist with a Novel Mechanism of Ligand Bias Functional characterization of the 5-oxo-ETE receptor OXE-R and identification of the first small molecule antagonist with a novel mechanism of ligand bias Dissertation zur Erlangung des Doktorgrades (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Stefanie Blättermann aus Düsseldorf Bonn 2011 Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms Universität Bonn. 1. Gutachter: Prof. Dr. Evi Kostenis 2. Gutachter: Prof. Dr. Klaus Mohr Tag der Promotion: 07.10.2011 Erscheinungsjahr: 2011 Die vorliegende Arbeit wurde in der Zeit von Oktober 2006 bis November 2010 am Institut für Pharmazeutische Biologie der Rheinischen Friedrich-Wilhelms Universität Bonn unter der Leitung von Frau Prof. Dr. Evi Kostenis durchgeführt. Meinen Eltern Index I Index Index .................................................................................................................................. I 1 Introduction ............................................................................................................... 1 1.1 G protein coupled receptors ............................................................................... 1 1.2 G proteins ........................................................................................................... 2 1.3 GPCR signaling ................................................................................................. 3 1.4 5-oxo-eicosatetraenioc acid ............................................................................... 4 1.5 5-oxo-ETE receptor ........................................................................................... 6 1.6 Aim of this work ................................................................................................ 7 2 Material and methods ............................................................................................... 9 2.1 Material .............................................................................................................. 9 2.1.1 Chemicals, enzymes and reagents ......................................................... 9 2.1.2 Kits ....................................................................................................... 11 2.1.3 Devices ................................................................................................. 11 2.1.4 Buffers and solutions ........................................................................... 12 2.1.5 Consumables ........................................................................................ 16 2.1.6 Software ............................................................................................... 17 2.1.7 Bacteria ................................................................................................ 18 2.1.8 Vectors ................................................................................................. 18 2.1.9 Mammalian cell lines ........................................................................... 19 2.2 Methods ........................................................................................................... 20 2.2.1 Molecular biology protocols ................................................................ 20 2.2.2 Cell culture protocols ........................................................................... 22 2.2.3 Cell based assays ................................................................................. 28 2.2.4 Computational modeling ...................................................................... 35 3 Results ...................................................................................................................... 37 3.1 OXE-R antagonist screening in calcium mobilization assays ......................... 37 3.1.1 Determination of calcium mobilization capabilities of the OXE-R in HEK293 cells ................................................................................... 37 3.1.2 OXE-R antagonist screening of a compound library in calcium mobilization assays .............................................................................. 39 3.1.3 Elucidation of unspecific cellular effects of Gü 1157 and Gü 1158 .... 40 3.1.4 Computational modeling of compounds with antagonistic activity on the OXE-R devoid of unspecific cellular effects ............................ 41 3.1.5 OXE-R antagonist screening of compounds derived from fragment based synthesis of compound 11852816 .............................. 45 3.1.6 Characterization of the nature of antagonism of Gü 1157, Gü 1158 and Gü 1654 in calcium mobilization assays ....................................... 46 II Index 3.1.7 Discussion ............................................................................................ 47 3.2 Investigations of antagonistic activity of Gü 1157, Gü 1158 and Gü 1654 on the OXE-R Gi pathway in cAMP accumulation assays .............................. 49 3.2.1 Determination of Gi signaling of the OXE-R by cAMP accumulation assays ............................................................................. 49 3.2.2 Analysis of antagonistic activity of Gü 1157, Gü 1158 and Gü 1654 on the Gi pathway of the OXE-R ................................................. 50 3.2.3 Discussion ............................................................................................ 51 3.3 Investigations of the biased antagonism of Gü 1157, Gü 1158 and Gü 1654 on the OXE-R using DMR assays ........................................................... 54 3.3.1 Visualization of isolated OXE-R G16 signaling in DMR assays .......... 55 3.3.2 Investigations of the antagonism of Gü 1157, Gü 1158 and Gü 1654 on the G16 pathway of the OXE-R in DMR assays ..................... 56 3.3.3 Analysis of antagonistic activity of Gü 1654 on the Gi pathway of the OXE-R in DMR assays ........................................... 58 3.3.4 Analysis of specific antagonism of Gü 1654 on the G16 pathway of the OXE-R ........................................................................ 58 3.3.5 Discussion ............................................................................................ 60 3.4 Investigations of OXE-R β-Arrestin recruitment ............................................. 63 3.4.1 Investigations of OXE-R β-Arrestin recruitment ................................. 64 3.4.2 Investigations of antagonistic activity of Gü 1157, Gü 1158 and Gü 1654 on OXE-R β-Arrestin2 recruitment ....................................... 65 3.4.3 Investigations of the pharmacology of the OXE-R fused to Rluc in DMR assays .......................................................................................... 66 3.4.4 Investigations of OXE-R specific inhibition of β-Arrestin recruitment by Gü 1654 ........................................................................ 66 3.4.5 Discussion ............................................................................................ 67 3.5 Investigations of antagonistic activity of Gü 1654 on OXE-R signaling in human primary cells ......................................................................................... 70 3.5.1 Investigations of antagonistic activity of Gü 1654 on the OXE-R in neutrophil DMR assays ...................................................... 71 3.5.2 Analysis of Gü 1654 on Gi-mediated signaling of the OXE-R in human primary cells ............................................................................. 78 3.5.3 Discussion ............................................................................................ 84 4 Final discussion ........................................................................................................ 89 5 Summary .................................................................................................................. 95 6 Abbreviations ........................................................................................................... 97 7 Literature ................................................................................................................. 99 8 Appendix ................................................................................................................ 113 Publications .................................................................................................................. 119 Curriculum vitae ......................................................................................................... 121 Index III Erklärung .................................................................................................................... 123 Acknowledgments ....................................................................................................... 125 1 Introduction 1 1 Introduction 1.1 G protein coupled receptors G protein coupled receptors (GPCRs) are signaling proteins which are found on the cell surface and transduce signals from outside the cell to the inside of a cell, thus allowing communication between cells, tissues and organs by responding to a wide range of modulators, such as hormones, neurotransmitters, lipids, peptides, nucleotides, ions and photons (Gether and Kobilka, 1998; Lagerström et al., 2008). With about 800 receptors, GPCRs represent the largest gene family in the mammalian genome, and, as widely expressed in the human body, GPCRs are involved in a vast range of physiologic and pathologic processes relying on cell signaling (Lundstrom, 2006). Related to their involvement
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