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J Biol Chem, Vol. 274, Issue 27, 19487-19497, July 2, 1999
From the Laboratory of Bioorganic Chemistry, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892
Several studies suggest, but do not prove
directly, that muscarinic receptors may be able to form dimeric or
oligomeric arrays. To address this issue in a more direct fashion, we
designed a series of biochemical experiments using a modified version
of the rat m3 muscarinic receptor (referred to as m3') as a model system. When membrane lysates prepared from m3' receptor-expressing COS-7 cells were subjected to Western blot analysis under non-reducing conditions, several immunoreactive species were observed corresponding in size to putative receptor monomers, dimers, and oligomers. However,
under reducing conditions, the monomeric receptor species represented
the only detectable immunoreactive protein, consistent with the
presence of disulfide-linked m3 receptor complexes. Similar results
were obtained when native m3 muscarinic receptors present in rat brain
membranes were analyzed. Control experiments carried out in the
presence of high concentrations of the SH group alkylating agent,
N-ethylmaleimide, suggested that disulfide bond formation did not occur artifactually during the preparation of cell lysates. The
formation of m3' receptor dimers/multimers was confirmed in coimmunoprecipitation studies using differentially epitope-tagged m3'
receptor constructs. In addition, these studies showed that m3'
receptors were also able to form non-covalently associated receptor
dimers and that m3' receptor dimer formation was receptor subtype-specific. Immunological studies also demonstrated that m3'
receptor dimers/multimers were abundantly expressed on the cell
surface. Site-directed mutagenesis studies indicated that two conserved
extracellular Cys residues (Cys-140 and Cys-220) play key roles in the
formation of disulfide-linked m3' receptor dimers. These results
provide the first direct evidence for the existence of muscarinic
receptor dimers and highlight the specificity and molecular diversity
of G protein-coupled receptor dimerization/oligomerization.
Identification and Molecular Characterization of m3
Muscarinic Receptor Dimers
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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