Molecular aspects of muscarinic receptor dimerization

The five muscarinic acetylcholine receptors (M(1)-M(5)) are prototypical members of the superfamily of G-protein-coupled receptors (GPCRs). During the past decade, this laboratory has used different members of this receptor subfamily as model systems to study the molecular mechanisms involved in GPCR function. This article reviews recent investigations dealing with molecular aspects of M(3) muscarinic receptor assembly and dimerization/oligomerization. Studies with coexpressed M(3) receptor fragments and M(3) muscarinic/alpha(2C)-adrenergic hybrid receptors showed that muscarinic receptors, like other GPCRs, are composed of multiple autonomous folding domains. Moreover, biochemical studies have provided direct evidence for the formation of M(3) receptor dimers/oligomers. These high molecular mass receptor species are expressed on the cell surface and can bind muscarinic ligands. M(3) receptor dimerization/oligomerization appears to be receptor subtype-selective and involves both non-covalent interactions as well as disulfide-crosslinking of receptor monomers. These studies add to the growing number of reports suggesting the existence of GPCR dimers or multimers. The precise functional characteristics of such receptor aggregates remain to be elucidated.