Domain Swapping in the Human Histamine H1 Receptor

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Abstract
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 H1 receptor. We also show the presence of domain-swapped H1 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 aspartate107 in transmembrane (TM) 3 or phenylalanine432 in TM6 to alanine results in two radioligand-binding-deficient mutant H1 receptors. Coexpression of H1D107 A and H1F432A, however, results in a reconstituted radioligand binding site that exhibits a pharmacological profile that corresponds to the wild-type H1 receptor. Interestingly, the H1 receptor radioligands [3H]mepyramine and [3H]-(–)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene show differential saturation binding values (Bmax) for wild-type H1 receptors but not for the radioligand binding site that is formed upon coexpression of H1 D107A and H1 F432A receptors, suggesting the presence of different H1 receptor populations.

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