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Evolutionary and Pharmacological Studies of NPY and QRFP Receptors

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Evolutionary and Pharmacological Studies of NPY and QRFP Receptors Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1040 Evolutionary and Pharmacological Studies of NPY and QRFP Receptors BO XU ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9059-1 UPPSALA urn:nbn:se:uu:diva-233461 2014 Dissertation presented at Uppsala University to be publicly examined in C2, 305, Husargatan 3, BMC, Uppsala, Friday, 21 November 2014 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Adjunct professor Samuel Svensson (Linköping University). Abstract Xu, B. 2014. Evolutionary and Pharmacological Studies of NPY and QRFP Receptors. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1040. 59 pp. Uppsala, Sweden: Acta Universitatis Upsaliensis. ISBN 978-91-554-9059-1. The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions. The NPY system was studied in zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and sea lamprey (Petromyzon marinus). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization. A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, Branchistoma floridae, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals. Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours. In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY- family receptors. Keywords: Neuropeptide Y, genome duplication, Evolution, vertebrate, Pharmacology, Modelling, Kinetics Bo Xu, Department of Neuroscience, Box 593, Uppsala University, SE-75124 Uppsala, Sweden. © Bo Xu 2014 ISSN 1651-6206 ISBN 978-91-554-9059-1 urn:nbn:se:uu:diva-233461 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233461) 博学之，审问之，慎思之，明辨之，笃行之。 ------《礼记·中庸》 Learn extensively, inquire thoroughly, ponder prudently, discriminate clearly and practice de- votedly. ------ Doctrine of the Mean List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Xu B, Sundström G, Kuraku S, Lundell I, Larhammar D. (2012) Clon- ing and pharmacological characterization of the neuropeptide Y recep- tor Y5 in the sea lamprey, Petromyzon marinus. Peptides 39: (64-70). II Xu B, Lagman D, Sundstrom G, Larhammar D. Neuropeptide Y fam- ily receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: clon- ing and pharmacological characterization. (Manuscript) III Sundström G, Xu B, Larsson TA, Heldin J, Bergqvist CA, Fredriks- son R, Conlon JM, Lundell I, Denver RJ, Larhammar D. (2012) Char- acterization of the neuropeptide Y system in the frog Silurana tropi- calis (Pipidae): three peptides and six receptor subtypes. Gen Comp Endocrinol 177(3):322-31. IV Sundström G, Larsson TA, Xu B, Heldin J, Larhammar D. (2013) Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b. Front Neurosci 7:29. V Xu B, Lundell I, Larhammar D. Characterization of QRFP peptide and its receptor from amphioxus, Branchiostoma floridae. (Submitted) VI Larhammar D, Xu B, Bergqvist CA. (2014) Unexpected multiplicity of QRFP receptors in early vertebrate evolution. (Front Neurosci, in press) VII Xu B, Fällmar H, Boukharta L, Pruner J, Lundell I, Mohell N, Gutiérrez-de-Terán H, Aqvist J, Larhammar D. (2013) Mutagenesis and computational modeling of human G-protein-coupled receptor Y2 for neuropeptide Y and peptide YY. Biochemistry 52: 7987-7998. VIII Xu B, Varasteh Z, Orlova A, Andersson K, Larhammar D, Björkelund H. (2013) Detecting ligand interactions with G protein-coupled recep- tors in real-time on living cells. Biochem Biophys Res Commun 441(4):820-4. Reprints were made with permission from the respective publishers Contents Introduction ................................................................................................... 11 Biological functions of the NPY system .................................................. 12 The mammalian NPY system .............................................................. 12 NPY system in other vertebrates ......................................................... 13 Evolution of the NPY and QRFP systems ................................................ 14 Whole genome duplications in vertebrates .......................................... 14 Evolution of NPY peptides .................................................................. 15 Evolution of NPY receptors ................................................................. 17 Evolution of the QRFP system ............................................................ 20 Structure of NPY family peptides and receptors ...................................... 21 Structure of NPY family peptides ........................................................ 21 Structure and pharmacology of GPCRs ............................................... 23 Structure of NPY receptors .................................................................. 25 Aims .............................................................................................................. 29 Materials and methods .................................................................................. 30 Sequence identification and analysis ........................................................ 30 Sequence identification ........................................................................ 30 Phylogenetic and synteny analysis ...................................................... 30 Tissue expression of cloned peptide and receptor genes .......................... 31 Homology modeling and docking ............................................................ 31 Molecular cloning and mutagenesis ......................................................... 31 Transfection .............................................................................................. 32 Ligands ..................................................................................................... 32 Pharmacological studies ........................................................................... 33 Binding assays ..................................................................................... 33 Inositol phosphate assay ...................................................................... 33 Ligand binding kinetics ....................................................................... 34 Data analysis ........................................................................................ 34 Results and discussion .................................................................................. 35 Paper I and II ............................................................................................ 35 Paper III .................................................................................................... 36 Paper IV ................................................................................................... 37 Paper V and VI ......................................................................................... 37 Paper VII .................................................................................................. 38 Paper VIII ................................................................................................. 40 Concluding remarks and future perspectives ................................................ 42 Acknowledgements ....................................................................................... 44 References ..................................................................................................... 46 Abbreviations AP Area postrema ARC Arcuate nucleus Bmax Maximum binding capacity BLAST Basic
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