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Molecular Evolution of G Protein-Coupled Receptors – Insights Into the Orexin System

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Molecular Evolution of G Protein-Coupled Receptors – Insights Into the Orexin System MAIJU RINNE Recent Publications in this Series 46/2019 Suvi Koskinen Near-Occlusive Atherosclerotic Carotid Artery Disease: Study with Computed Tomography Angiography 47/2019 Flavia Fontana THE OREXIN SYSTEM INTO — INSIGHTS RECEPTORS OF G PROTEIN-COUPLED EVOLUTION MOLECULAR Biohybrid Cloaked Nanovaccines for Cancer Immunotherapy 48/2019 Marie Mennesson Kainate Receptor Auxiliary Subunits Neto1 and Neto2 in Anxiety and Fear-Related Behaviors DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM 49/2019 Zehua Liu UNIVERSITATIS HELSINKIENSIS Porous Silicon-Based On-Demand Nanohybrids for Biomedical Applications 50/2019 Veer Singh Marwah Strategies to Improve Standardization and Robustness of Toxicogenomics Data Analysis 51/2019 Iryna Hlushchenko Actin Regulation in Dendritic Spines: From Synaptic Plasticity to Animal Behavior and Human Neurodevelopmental Disorders 52/2019 Heini Liimatta Effectiveness of Preventive Home Visits among Community-Dwelling Older People MAIJU RINNE 53/2019 Helena Karppinen Older People´s Views Related to Their End of Life: Will-to-Live, Wellbeing and Functioning 54/2019 Jenni Laitila MOLECULAR EVOLUTION OF G PROTEIN-COUPLED Elucidating Nebulin Expression and Function in Health and Disease RECEPTORS — INSIGHTS INTO THE OREXIN SYSTEM 55/2019 Katarzyna Ciuba Regulation of Contractile Actin Structures in Non-Muscle Cells 56/2019 Sami Blom Spatial Characterisation of Prostate Cancer by Multiplex Immunohistochemistry and Quantitative Image Analysis 57/2019 Outi Lyytinen Molecular Details of the Double-Stranded RNA Virus Replication and Assembly 58/2019 Markus Räsänen Vascular Endothelial Growth Factor-B and the Bmx Tyrosine Kinase in Cardiac Hypertrophy and Revascularization 59/2019 Vuokko Nummi Insights into Clinical and Laboratory Phenotypes of Von Willebrand Disease 60/2019 Shah Hasan Challenges of Hyper-Prolificacy in the Pig: Colostrum and Gut Microbiota 61/2019 Sanna Matilainen Pathomechanisms of Leigh Syndrome: Defects of Post-Transcriptional and Post-Translational Regulation of Mitochondrial Metabolism 62/2019 Kirsi Santti Desmoid Tumor: Oncological Management and Prognostic Biomarkers 63/2019 Hesham E. Abdolhfid Mohamed Evaluation of Prognostic Markers for Oropharyngeal Carcinoma Using Tissue Microarray 64/2019 Johanna Uhari-Väänänen Contributions of µ- and κ-Opioidergic Systems to Ethanol Intake and Addiction 65/2019 Susanna Rapo-Pylkkö DIVISION OF PHARMACEUTICAL CHEMISTRY AND TECHNOLOGY Chronic Pain and Neuropathic Pain among Community-dwelling Older Adults in Primary Health FACULTY OF PHARMACY Care Settings 66/2019 Helka Göös DOC­TORAL PRO­GRAMME IN IN­TEG­RAT­IVE LIFE SCIENCE Human Transcription Factor Protein-protein Interactions in Health and Disease UNIVERSITY OF HELSINKI 67/2019 Helsinki 2019 ISSN 2342-3161 ISBN 978-951-51-5468-2 Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki Finland Molecular evolution of G protein-coupled receptors – insights into the orexin system Maiju K. Rinne ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Pharmacy, University of Helsinki, for public examination in the Auditorium 1041, Biocentre 2, on September 27th 2019, at 12 o’clock. Helsinki 2019 Supervisors Docent Henri Xhaard, PhD Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki, Finland Professor Jyrki Kukkonen, PhD Department of Veterinary Biosciences Faculty of Veterinary Medicine University of Helsinki, Finland Reviewers Docent Juha Savinainen, PhD Institute of Biomedicine University of Eastern Finland, Finland Docent Tiina Salminen, PhD Structural Bioinformatics Laboratory Biochemistry, Faculty of Science and Engineering Åbo Akademi University, Finland Opponent Senior Scientist Xavier Deupi i Corral, PhD Laboratory for Scientific Computing and Modelling Paul Scherrer Institute, Switzerland © Maiju Rinne 2019 ISBN 978-951-51-5468-2 (paperback) ISBN 978-951-51-5469-9 (PDF, http://ethesis.helsinki.fi) Published in the DSHealth series Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis ISSN 2342-3161 (print) ISSN 2342-317X (online) Hansaprint, Vantaa, Finland, 2019 Abstract The diversity of G protein-coupled receptors is a fundamental element in this thesis. GPCRs are the largest family of membrane proteins, with about 800 in humans. While the human GPCR repertoire is well described, in other species, especially in non-mammals, GPCRs are not tracked to the individual subtype level in large-scale genomic studies. The diversity of GPCRs in non-human vertebrates was studied in the first publication. The study classified 142 rhodopsin-like non-olfactory GPCRs without human orthologue, 69 of which were reported for the first time. The study also points out inconsistencies in the GPCR nomenclature system and reveals a pool of yet-to-be studied receptors. Understanding the repertoire of GPCRs in non- human species might also be useful for many areas of science, such as pharmacology, ecotoxicology and evolutionary biology. For more insight into the orexin system, two small-molecule orexin receptor agonists were pharmacologically characterised in the second and third publications. Nag26 was confirmed to be a potent and almost full agonist of orexin receptors, but the selectivity for orexin receptor type-2 was not as strong as reported (20-fold against 70-fold). Yan7874 was also confirmed to be an orexin receptor agonist, but only partial and weak with high off-target activity. Neither of these compounds is likely to be suitable for further drug development as such. These studies also display the challenge in the development of small-molecule agonists for peptide-bound GPCRs. Finally, Ciona intestinalis putative orexin receptor was studied, and its functionality was verified in recombinant cells. Homology models of C. intestinalis orexin receptor revealed a highly similar binding cavity as in the human OX2 orexin receptor. Thus, the functionality of the receptor was studied in Ca2+ elevation assay, and the receptor was verified to be functional and binding to human orexin peptides. Further database mining resulted in the identification of putative C. intestinalis prepro-orexin and orexin peptide that was shown to bind to a plasma membrane of C. intestinalis orexin receptor-expressing cells. Solving the function of the orexin system in distinct species such as C. intestinalis might be interesting from an evolutionary point of view but also essential in extending the knowledge of the orexin system in humans. 4 This thesis was conducted collaboratively with the Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy and Department of Veterinary Biosciences, Faculty of Veterinary Medicine, at the University of Helsinki. 5 Tiivistelmä G-proteiinikytkentäisten reseptorien moninaisuus on keskiössä tässä väitöskirjatyössä. G-proteiinikytkentäiset reseptorit ovat suurin yhtenäinen kalvoreseptorien ryhmä, ja ihmisellä on noin 800 G-proteiinikytkentäistä reseptoria. Toisin kuin ihmisen reseptorien kohdalla, muiden lajien edustajien (varsinkin nisäkkäiden ulkopuolelta) reseptorijoukkoa on harvoin jäljitetty alatyyppitasolle asti laajoissa genomitutkimuksissa. Tämän väitöskirjatyön ensimmäinen julkaisu perehtyy G- proteiinikytkentäisten reseptorien moninaisuuteen selkärankaisilla lajeilla. Tutkimus luokittelee 142 rodopsiini-reseptorien ryhmään kuuluvaa G-proteiinikytkentäistä reseptoria ilman humaania ortologia. Näistä reseptoreista 69 esitetään tässä työssä ensimmäistä kertaa. Lisäksi tutkimus osoittaa reseptorien epäjohdonmukaisuuksia nimeämissysteemissä, sekä esittelee vielä tutkimattomia reseptoreja. Laajempi ymmärrys eri lajien reseptorirepertuaarista voi olla hyödyllinen monilla tieteenaloilla, kuten farmakologiassa, ekotoksikologiassa ja evoluutiobiologissa. Tässä väitöskirjatyössä tutkittiin myös ihmisen G-proteiinikytkentäisiä reseptoreja. Kahden pienmolekyylioreksiinireseptoriagonistin ominaisuudet luokiteltiin farmakologisesti tämän väitöskirjan toisessa ja kolmannessa julkaisussa. Tutkimus vahvisti pienmolekyyli Nag26:n olevan potentti, lähes täysagonisti ja selektiivinen tyypin-2 oreksiinireseptorille, joskaan ei yhtä voimakkaasti selektiivinen kuin aikaisemmin on raportoitu. Pienmolekyyli Yan7874:n vahvistettiin olevan myös oreksiinireseptoriagonisti, mutta vain osittainen ja heikko. Lisäksi, Yan7874 indusoi soluissa epäspesifisiä vaikutuksia. On siis epätodennäköistä, että kumpikaan näistä yhdisteistä tarjoaisi sellaisenaan potentiaalia pidemmälle lääkekehitykselle. Nämä tutkimukset osoittavat osaltaan pienmolekyyliagonistien kehityksen haasteita peptideihin sitoutuviin G-proteiinikytkentäistiin reseptoreihin. Lopuksi, tässä työssä tutkittiin selkärangattoman Ciona intestinalis –lajin putatiivista oreksiinireseptoria, ja sen toiminnallisuus vahvistettiin ilmentämällä sitä rekombinanteissa soluissa. Homologiamallien perusteella reseptorin sitoutumistaskun osoitettiin muistuttavan ihmisen tyyppi-2 oreksiinireseptorin sitoutumistaskua. Oreksiinireseptorin toimivuus vahvistettiin reseptori-riippuvaisella solunsisäisen kalsiumin mobilisaatiolla, ja sitovan humaaneja oreksiinipeptidejä. Lisäksi tietokantalouhinta johti putatiivisen C. intestinalis oreksiini-prekursorin ja oreksiinipeptidin tunnistamiseen. Tässä väitöskirjatyössä tunnistettiin ensimmäistä 6 kertaa C. intestinalis –lajin oreksiini-prekursori ja osoitettiin, että putatiivinen oreksiinipeptidi sitoutuu C. intestinalis oreksiinireseptoria expressoivien solujen solukalvolle.
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