Agonist occupancy of a single monomeric element is sufficient to cause internalization of the dimeric beta(2)-adrenoceptor

Sartania, N. , Appelbe, S., Pediani, J. D. and Milligan, G. (2007) Agonist occupancy of a single monomeric element is sufficient to cause internalization of the dimeric beta(2)-adrenoceptor. Cellular Signalling, 19, pp. 1928-1938. (doi: 10.1016/j.cellsig.2007.05.002)

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A range of studies have indicated that many rhodopsin-like, family A G protein-coupled receptors, including the β2-adrenoceptor, exist and probably function as dimers. It is less clear if receptors internalize as dimers and if agonist occupancy of only one element of a dimer is sufficient to cause internalization of a receptor dimer into the cell. We have used a chemogenomic approach to demonstrate that this is the case. Following expression of the wild type β2-adrenoceptor, isoprenaline but not 1-(3′'4′-dihydroxyphenyl)-3-methyl-1-butanone, which does not have significant affinity for the wild type receptor, caused receptor internalization. By contrast, 1-(3′4′-dihydroxyphenyl)-3-methyl-1-butanone, but not isoprenaline that does not have high affinity for the mutated receptor, caused internalization of Asp113Serβ2-adrenoceptor. Following co-expression of wild type and Asp113Serβ2-adrenoceptors each of isoprenaline and 1-(3′4′-dihydroxyphenyl)-3-methyl-1-butanone caused the co-internalization of both of these two forms of the receptor. Co-expressed wild type and Asp113Serβ2-adrenoceptors were able to be co-immunoprecipitated and 1-(3′4′-dihydroxyphenyl)-3-methyl-1-butanone produced internalization of the wild type receptor that was not prevented by the β-adrenoceptor antagonist propranolol that binds with high affinity only to the wild type receptor. These results demonstrate that agonist occupancy of either single binding site of the β2-adrenoceptor dimer is sufficient to cause internalization of the dimer and that antagonist occupation of one of the two ligand binding sites is unable to prevent agonist-mediated internalization.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Appelbe, Mrs Shirley and Pediani, Dr John and Sartania, Dr Nana
Authors: Sartania, N., Appelbe, S., Pediani, J. D., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Cellular Signalling
ISSN (Online):1873-3913
Published Online:18 May 2007

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