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Domain swapping in the human histamine H-1 receptor

Bakker, R. A., Dees, G., Carrillo, J. J., Booth, R. G., Lopez-Gimenez, J. F., Milligan, G., Strange, P. G. and Leurs, R. (2004) Domain swapping in the human histamine H-1 receptor. Journal of Pharmacology and Experimental Therapeutics, 311 (1). pp. 131-138. ISSN 0022-3565

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To link to this item DOI: 10.1124/jpet.104.067041

Abstract/Summary

G-protein-coupled receptors (GPCRs) represent the largest family of receptors involved in transmembrane signaling. Although these receptors were generally believed to be monomeric entities, accumulating evidence supports the presence of GPCRs in multimeric forms. Here, using immunoprecipitation as well as time-resolved fluorescence resonance energy transfer to assess protein-protein interactions in living cells, we unambiguously demonstrate the occurrence of dimerization of the human histamine H-1 receptor. We also show the presence of domain-swapped H-1 receptor dimers in which there is the reciprocal exchange of transmembrane domain TM domains 6 and 7 between the receptors present in the dimer. Mutation of aspartate(107) in transmembrane (TM) 3 or phenylalanine(432) in TM6 to alanine results in two radioligand-binding-deficient mutant H-1 receptors. Coexpression of H-1 D(107)A and H-1 F(432)A, however, results in a reconstituted radioligand binding site that exhibits a pharmacological profile that corresponds to the wildtype H-1 receptor. Interestingly, the H-1 receptor radioligands [H-3] mepyramine and [H-3]-(-)- trans-1-phenyl-3-N, N-dimethylamino-1,2,3,4-tetrahydronaphthalene show differential saturation binding values (B-max) for wild-type H-1 receptors but not for the radioligand binding site that is formed upon coexpression of H-1 D(107)A and H-1 F(432)A receptors, suggesting the presence of different H-1 receptor populations.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Biological Sciences
ID Code:10419
Uncontrolled Keywords:PROTEIN-COUPLED RECEPTORS, RESONANCE ENERGY-TRANSFER, DOPAMINE D2, RECEPTOR, OPIOID RECEPTORS, RAT-BRAIN, CONSTITUTIVE OLIGOMERIZATION, MUSCARINIC RECEPTORS, BINDING-PROPERTIES, LIGAND-BINDING, TRANSFER BRET

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