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Further evidence for ancient role of ACTH peptides at melanocortin (MC) receptors; pharmacology of dogfish and lamprey peptides at dogfish MC receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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2007 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, no 4, 798-805 p.Article in journal (Refereed) Published
Abstract [en]

The cloning of melanocortin (MC) receptors in distant species has provided us tools to get insight in how the ligand–receptors interactions in the MC system have evolved. We have however lacked studies on pharmacology of native ancient melanocortin peptides at the ancient MC receptors. In this paper we synthesized melanocortin peptides from both the sea lamprey (Petromyzon marinus) and spiny dogfish (Squalus acanthias) and tested them on the MC3 and MC4 receptors from spiny dogfish. The results show that both the dogfish and lamprey ACTH peptides have similar or higher affinity than the dogfish α-, β- and γ-MSH peptides to the dogfish MC3 and MC4 receptors. Moreover, both the dogfish and lamprey ACTH peptides have more than 10-fold higher affinity than α-MSH to the dogfish MC4 receptor. We also show that dogfish δ-MSH is able to bind to MC receptors and its potency is higher than of dogfish β-MSH, which is considered to be its precursor. Our results provide the first evidence that native ACTH ligands from dogfish and lamprey have a preference above native MSH peptides to ancient version of the MC3 and MC4 receptors. This further strengthens the hypotheses that the ligand contributing to the first version of the melanocortin ligand-receptor system resembled ACTH.

Place, publisher, year, edition, pages
2007. Vol. 28, no 4, 798-805 p.
Keyword [en]
δ-MSH, ACTH, Dogfish, Melanocortin, Neofunctionalization, Subfunctionalization
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-16305DOI: 10.1016/j.peptides.2006.12.015ISI: 000245625900011PubMedID: 17306418OAI: oai:DiVA.org:uu-16305DiVA: diva2:44076
Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2017-12-08Bibliographically 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, Tatjana

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