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Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
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2005 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 512, no 2-3, 85-95 p.Article in journal (Refereed) Published
Abstract [en]

This study evaluates the binding the melanocyte stimulating hormone peptide analogue [125I]NDP-MSH to melanocortin receptors MC1, MC3, MC4 and MC5 in insect cell membranes produced by baculovirus expression systems. The presence of Ca2+ was found to be mandatory to achieve specific [125I]NDP-MSH binding to the melanocortin receptors. Although association kinetics of [125I]NDP-MSH followed the regularities of simple bimolecular reactions, the dissociation of [125I]NDP-MSH from the melanocortin receptors was heterogeneous. Eleven linear and cyclic MSH peptides studied displaced the [125I]NDP-MSH binding to the studied melanocortin receptors, with the shapes of their competition curves varying from biphasic or shallow to super-steep (Hill coefficients ranging from 0.4 to 1.5). Notably the same peptide often gave highly different patterns on different melanocortin receptor subtypes; e.g. the MC4 receptor selective antagonist HS131 gave a Hill coefficient of 1.5 on the MC1 receptor but 0.5-0.7 on the MC(3-5) receptors. Adding a mask of one of the peptides to block its high affinity binding did not prevent other competing peptides to yield biphasic competition curves. The data indicate that the binding of MSH peptides to melanocortin receptors are governed by a complex dynamic homotropic co-operative regulations.

Place, publisher, year, edition, pages
2005. Vol. 512, no 2-3, 85-95 p.
Keyword [en]
Animals, Binding Sites, Binding; Competitive/drug effects, Calcium/pharmacology, Cell Line, Cell Line; Tumor, Cell Membrane/metabolism, Comparative Study, Dose-Response Relationship; Drug, Iodine Radioisotopes, Kinetics, Ligands, Melanoma; Experimental/metabolism/pathology, Peptides; Cyclic/metabolism/pharmacology, Radioligand Assay, Receptor; Melanocortin; Type 1/metabolism, Receptor; Melanocortin; Type 3/metabolism, Receptor; Melanocortin; Type 4/metabolism, Receptors; Melanocortin/*metabolism, Research Support; Non-U.S. Gov't, Spodoptera, Time Factors, alpha-MSH/*analogs & derivatives/metabolism, gamma-MSH/metabolism/pharmacology
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-104280DOI: 10.1016/j.ejphar.2005.02.021PubMedID: 15840392OAI: oai:DiVA.org:uu-104280DiVA: diva2:219589
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved

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