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      Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites.

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          Abstract

          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.

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          Author and article information

          Journal
          Eur. J. Pharmacol.
          European journal of pharmacology
          Elsevier BV
          0014-2999
          0014-2999
          Apr 11 2005
          : 512
          : 2-3
          Affiliations
          [1 ] Department of Pharmaceutical Biosciences, Uppsala University, BMC Box 591, 751 24 Uppsala, Sweden.
          Article
          S0014-2999(05)00180-9
          10.1016/j.ejphar.2005.02.021
          15840392
          c6d44b19-7591-4122-81a7-a44da8d944d5
          History

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