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Neuropeptide Y/peptide YY receptor Y2 duplicate in zebrafish with unique introns displays distinct peptide binding properties
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
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2011 (English)In: Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology, ISSN 1096-4959, E-ISSN 1879-1107, Vol. 160, no 4, 166-173 p.Article in journal (Other academic) Published
Abstract [en]

The neuropeptide Y-family peptides and receptors are involved in a broad range of functions including appetite regulation. Both the peptide genes and the receptor genes are known to have duplicated in early vertebrate evolution. The ancestral jawed vertebrate had 7 NPY receptors but the number varies between 4 and 7 in extant vertebrates. Herein we describe the identification of an additional NPY receptor in two fish species, zebrafish and medaka. They cluster together with the Y2 receptors in phylogenetic analyses and seem to be orthologous to each other that is why we have named them Y2-2. Their genes differ from Y2 in having introns in the coding region. Binding studies with zebrafish Y2-2 receptors show that the three endogenous peptides NPY, PYYa and PYYb have similar affinities, 0.15-0.66nM. This is in contrast to the Y2 receptor where they differed considerably from one another. N-terminally truncated NPY binds poorly and the Y2 antagonist BIIE0246 binds well to Y2-2, results that are reversed in comparison to Y2. Zebrafish Y2-2 mRNA was detected by PCR in the intestine and the eye, but not in the brain. In conclusion, we have found a novel Y2-like NPY/PYY receptor that probably arose in early teleost fish evolution.

Place, publisher, year, edition, pages
2011. Vol. 160, no 4, 166-173 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-154990DOI: 10.1016/j.cbpb.2011.08.001ISI: 000296679800004PubMedID: 21855645OAI: oai:DiVA.org:uu-154990DiVA: diva2:432636
Available from: 2011-08-04 Created: 2011-06-14 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Studies of the Neuropeptide Y Receptor Y2 in Human and Zebrafish
Open this publication in new window or tab >>Studies of the Neuropeptide Y Receptor Y2 in Human and Zebrafish
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The G-protein coupled receptors (GPCRs) comprise the largest family of receptors in humans and other vertebrates. They are embedded in the cell membrane and are activated by many different signaling molecules. Activation modulates cellular signal transduction pathways and influences many physiological processes. Therefore the GPCRs are important as targets for numerous drugs.

The receptors for NPY (neuropeptide Y) belong to GPCRs of Class A (rhodopsin-like). NPY and its related peptides PYY and PP are involved in the regulation of appetite, blood pressure and many other processes. They share a common structure and interact with the receptors Y1, Y2, Y4 and Y5 in mammals, and, in addition, Y7 and Y8 in amphibians and bony fishes.

This thesis is focused on the human Y2 receptor, known to reduce appetite, by investigating the importance of thirteen amino acid residues for ligand binding. Mutagenesis followed by functional expression and receptor binding was conducted. During the course of this work several new GPCR crystal structures have been resolved, thereby improving the receptor modeling in papers I-III. The major finding is that even though the Y1 and Y2 receptors have evolved from a common ancestor, their points of ligand interaction differ and have thus changed during evolution. In general, the positions investigated resulted in milder changes in the ligands’ affinities for Y2 compared to Y1. These findings were incorporated in the design of new Y1 and Y2 receptor models, leading to improved understanding of how such divergent receptors, sharing only 30 percent sequence identity, can still interact with the same ligands. Notably, several of the mutations introduced in Y2 resulted in increased affinity.

A novel NPY receptor gene named Y2-2 was identified in the genomes of zebrafish and medaka. This brings the number of zebrafish NPY receptors to seven. The binding characteristics of zebrafish Y2-2 differed from zebrafish Y2 mainly in the interaction with NPY13-36 and the antagonist BIIE0246.

In conclusion, these results increase our understanding of ligand interactions with GPCRs and will be useful for refinement of ligand-receptor models for future development of receptor subtype-selective drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 687
Keyword
Y2-receptor, NPY, PYY, G-protein-coupled receptor, mutagenesis, receptor binding, zebrafish, evolution
National Category
Pharmacology and Toxicology
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-156635 (URN)978-91-554-8117-9 (ISBN)
Public defence
2011-09-21, B:41, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2011-08-31 Created: 2011-08-04 Last updated: 2011-09-08Bibliographically approved

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Fällmar, HelenaSundström, GörelLundell, IngridMohell, NinaLarhammar, Dan

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