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High-Affinity Interactions between Human _1A-Adrenoceptor C-Terminal Splice Variants Produce Homo- and Heterodimers but Do Not Generate the _1L-Adrenoceptor

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (D.R., I.C.C., J.P., J.F.L.-G., G.M.); and Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (R.T., M.F.)

Using combinations of bioluminescence resonance energy transfer, time-resolved fluorescence resonance energy transfer and the functional complementation of pairs of inactive receptor-G protein fusion proteins, the human _1A-1-adrenoceptor was shown to form homodimeric/oligomeric complexes when expressed in human embryonic kidney (HEK) 293 cells. Saturation bioluminescence resonance energy transfer studies indicated the _1A-1-adrenoceptor homodimer interactions to be high affinity and some 75 times greater than interactions between the _1A-1-adrenoceptor and the opioid peptide receptor. Only a fraction of the _1A-1-adrenoceptors was at the plasma membrane of HEK293 cells at steady state. However, dimers of _1A-1-adrenoceptors were also present in intracellular membranes, and the dimer status of those delivered to the cell surface was unaffected by the presence of agonist. Splice variation can generate at least three forms of the human _1A-1-adrenoceptor with differences limited to the C-terminal tail. Each of the _1A-1, _1A-2a, and _1A-3a-adrenoceptor splice variants formed homodimers/oligomers, and all combinations of these splice variants were able to generate heterodimeric/oligomeric interactions. Despite the coexpression of these splice variants in human tissues that possess the pharmacologically defined _1L-adrenoceptor binding site, coexpression of any pair in HEK293 cells failed to generate ligand binding characteristic of the _1L-adrenoceptor.

Address correspondence to: Dr. Graeme Milligan, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom. E-mail: g.milligan{at}bio.gla.ac.uk

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