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Structural model of human neuropeptide Y receptor Y1 based on interactions of mutated receptors with NPY and two antagonists
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-89540OAI: oai:DiVA.org:uu-89540DiVA: diva2:161092
Available from: 2001-11-01 Created: 2001-11-01 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Neuropeptide Y Receptors in Human, Guinea pig and Chicken: Cloning, in vitro Pharmacology and in situ Hybridization
Open this publication in new window or tab >>Neuropeptide Y Receptors in Human, Guinea pig and Chicken: Cloning, in vitro Pharmacology and in situ Hybridization
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuropeptide Y (NPY) is known to influence a vast number of physiological and behavioral processes such as vasoconstriction, circadian rhythms, feeding, anxiety and memory. Peptides of the NPY family bind to five different cloned G-protein coupled receptor subtypes (Y1, 2, 4-6). The studies compiled in this thesis present inter-species comparisons of sequence similarities, binding properties and expression patterns among receptors of the NPY family.

Cloning of Y1 and Y2 receptor subtypes from guinea pigs revealed strong binding profile similarity to the corresponding human receptors. Previously demonstrated atypical binding profiles in the caval vein of guinea pigs were concluded to result from other receptors than the cloned Y1 and Y2 receptors, or possibly combinations of distinct receptor subtypes.

The guinea pig Y5 receptor was found to be expressed in regions of the brain that have been indicated as important for regulation of food intake. Expression in the hypothalamus, amygdala and brain stem was noticed, similar to studies in rats and humans. In other brain regions, such as the striatum and hippocampus, some species differences were observed.

Mutagenesis studies of the human Y1 receptor indicated sites important for binding both of endogenous agonists and synthetic antagonists. Putative new sites of interaction with the Y1 antagonists BIBP3226 and/or SR120819A were recognized. The data were used to construct a three-dimensional structure model, based on a high-resolution bovine rhodopsin model.

Cloning of the chicken (Gallus gallus) Y1, Y2 and Y5 receptors revealed high sequence similarities with mammalian receptors. Most endogenous ligands bound with similar affinities as to mammalian receptors. The strongest exception was the discovery of high-affinity binding to chicken Y2 of [Leu31, Pro34]NPY, which was previously considered to bind non-Y2 receptors only.

The new human Y1 receptor model provides a basis for further investigations of ligand-receptor interactions which will be aided by information on NPY receptors from other taxa. Guinea pigs are concluded to be a good complement to rats and mice for studying NPY signaling. These results demonstrate the benefits of species comparisons for pharmacological studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 55 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1097
Neurosciences, G-protein coupled receptor, neuropeptide Y, neuropeptide Y receptor, ortholog, chicken, guinea pig, mutagenesis, receptor computer modeling, mRNA in situ hybridization, Neurovetenskap
National Category
Research subject
Medical Pharmacology
urn:nbn:se:uu:diva-1502 (URN)91-554-5160-8 (ISBN)
Public defence
2001-11-23, lecture hall B41, Biomedical Centre, Uppsala, 09:15
Available from: 2001-11-01 Created: 2001-11-01Bibliographically approved

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