Evolutionary and Pharmacological Studies of NPY and QRFP Receptors

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Xu, Bo,1980-Uppsala universitet,Institutionen för neurovetenskap,Pharmacology (författare)

Evolutionary and Pharmacological Studies of NPY and QRFP Receptors

BokEngelska2014

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Uppsala, Sweden :Acta Universitatis Upsaliensis,2014
59 s.
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-233461
ISBN:9789155490591
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233461URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;1040

Anmärkningar

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.

Ämnesord och genrebeteckningar

NATURVETENSKAP Biologi Evolutionsbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Evolutionary Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmakologi och toxikologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
NATURVETENSKAP Biologi Cellbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Cell Biology hsv//eng
NATURVETENSKAP Biologi Strukturbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Structural Biology hsv//eng
Neuropeptide Y
genome duplication
Evolution
vertebrate
Pharmacology
Modelling
Kinetics
Bioinformatik
Bioinformatics
Biology with specialization in Evolutionary Genetics
Biologi med inriktning mot evolutionär genetik
Biologi med inriktning mot evolutionär funktionsgenomik
Biology with specialization in Evolutionary Functional Genomics
Farmaceutisk farmakologi
Pharmaceutical Pharmacology

Biuppslag (personer, institutioner, konferenser, titlar ...)

Larhammar, Dan,ProfessorUppsala universitet,Institutionen för neurovetenskap (preses)
Svensson, Samuel,Adjunct professorLinköping University (opponent)
Uppsala universitetInstitutionen för neurovetenskap (creator_code:org_t)

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