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Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
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2004 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 380, no 2, 475-486 p.Article in journal (Refereed) Published
Abstract [en]

The rainbow trout (Oncorhynchus mykiss) is one of the most widely used fish species in aquaculture and physiological research. In the present paper, we report the first cloning, 3D (three-dimensional) modelling, pharmacological characterization and tissue distribution of two melanocortin (MC) receptors in rainbow trout. Phylogenetic analysis indicates that these receptors are orthologues of the human MC4 and MC5 receptors. We created 3D molecular models of these rainbow trout receptors and their human counterparts. These models suggest greater divergence between the two human receptors than between their rainbow trout counterparts. The pharmacological analyses demonstrated that ACTH (adrenocorticotropic hormone) had surprisingly high affinity for the rainbow trout MC4 and MC5 receptors, whereas alpha-, beta- and gamma-MSH (melanocyte-stimulating hormone) had lower affinity. In second-messenger studies, the cyclic MSH analogues MTII and SHU9119 acted as potent agonist and antagonist respectively at the rainbow trout MC4 receptor, indicating that these ligands are suitable for physiological studies in rainbow trout. Interestingly, we found that the rainbow trout MC4 receptor has a natural high-affinity binding site for zinc ions (0.5 microM) indicating that zinc may play an evolutionary conserved role at this receptor. Reverse transcription PCR indicates that the rainbow trout receptors are expressed both in peripheral tissues and in the central nervous system, including the telencephalon, optic tectum and hypothalamus. Overall, this analysis indicates that the rainbow trout MC4 and MC5 receptors have more in common than their mammalian counterparts, which may suggest that these two receptors have a closer evolutionary relationship than the other MC receptor subtypes.

Place, publisher, year, edition, pages
2004. Vol. 380, no 2, 475-486 p.
Keyword [en]
adrenocorticotropic hormone (ACTH), G-protein-coupled receptor (GPCR), hormone receptor, melanocortin, melanocyte-stimulating hormone (MSH), rainbow trout (Oncorhynchus mykiss)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-70125DOI: 10.1042/BJ20031934OAI: oai:DiVA.org:uu-70125DiVA: diva2:98036
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2017-11-21Bibliographically approved
In thesis
1. Function, Pharmacology, Evolution and Anatomical Localization of G Protein-Coupled Receptors and Solute Carriers
Open this publication in new window or tab >>Function, Pharmacology, Evolution and Anatomical Localization of G Protein-Coupled Receptors and Solute Carriers
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The G protein-coupled receptors (GPCRs) and solute carriers (SLC) are two large families of membrane-bound proteins. The aim of this study was to characterize these two families in terms of evolution and function. The melanocortin (MC) receptors belong to the Rhodopsin family of GPCRs and we cloned the MC4 and MC5 receptors from the rainbow trout, MC3 and MC5 from the spiny dogfish and MCa and MCb from the river lamprey. Pharmacological characterization of the cloned MC receptors demonstrated higher affinity for adrenocorticotropic hormone (ACTH) compared to melanocyte stimulating hormone (MSH) peptides (alpha-, beta- and gamma-MSH). We performed expression analysis with reverse transcription PCR, which showed that the MC4 and MC5 receptors in the rainbow trout are expressed centrally as well as in peripheral tissues. The dogfish MC3 and MC5 receptors were expressed in the brain, while the lamprey MCa and MCb receptors were expressed in the periphery. An extensive tissue localization analysis was performed for the entire family of Adhesion GPCRs in the rat and mouse. Using quantitative real-time PCR (qRT-PCR) we discovered that the majority of GPCRs were expressed either specifically in the CNS or ubiquitously in the CNS and peripheral tissues. We identified all non-olfactory GPCRs in the dog and classified them into Adhesion, Frizzled, Glutamate, Rhodopsin and Secretin families. The dog GPCR repertoire seemed to be more similar to the human repertoire than to the repertoires in rodents. Solute carrier family 25 includes mitochondrial membrane transporters. Using bioinformatics techniques we identified 14 novel members of the SLC25 family, which now has 46 members. We identified orthologs of the novel SLC25 family members in yeast and performed expression analysis of 9 of them with qRT-PCR on a panel containing 30 central and peripheral tissues from the rat. To conclude, this study has expanded our knowledge of the repertoire of genes coding for membrane-bound proteins and provided information about their functional roles.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 437
National Category
Pharmacology and Toxicology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-99413 (URN)978-91-554-7466-9 (ISBN)
Public defence
2009-04-24, Room B41, BMC, Uppsala, 09:15 (English)
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Available from: 2009-04-03 Created: 2009-03-13 Last updated: 2009-09-04Bibliographically approved

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Haitina, TatjanaFredriksson, RobertLagerström, Malin C.Larhammar, DanSchiöth, Helgi B.

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