AGPCR oligomer is aprotein complex that consists of a small number (ὀλίγοιoligoi "a few",μέροςméros "part, piece, component") ofG protein-coupled receptors (GPCRs). It is held together bycovalent bonds or byintermolecular forces. Thesubunits within this complex are calledprotomers, while unconnected receptors are called monomers. Receptor homomers consist of identical protomers, while heteromers consist of different protomers.
Receptor homodimers – which consist of two identical GPCRs – are the simplesthomomeric GPCR oligomers.Receptor heterodimers – which consist of two different GPCRs – are the simplestheteromeric GPCR oligomers.
The existence of receptoroligomers is a general phenomenon, whose discovery has superseded the prevailingparadigmatic concept of the function of receptors as plain monomers, and has far-reaching implications for the understanding of neurobiological diseases as well as for the development of drugs.[2][3]
For a long time it was assumed that receptors transmitted their effects exclusively from their basic functional forms – as monomers. The first clue to the existence of GPCR oligomers goes back to 1975 whenRobert Lefkowitz observed thatβ-adrenoceptors display negative bindingcooperativity.[4] At the beginning of the 1980s, it was hypothesized, receptors could form largercomplexes, the so-called mosaic form,[5] where two receptors may interact directly with each other.[6] Mass determination of β-adrenoceptors (1982)[7] andmuscarinic receptors (1983),[8] supported the existence ofhomodimer or tetrameric complexes. In 1991, the phenomenon ofreceptor crosstalk was observed betweenadenosine A2A (A2A) anddopamine D2 receptor (DRD2) thus suggesting the formation of heteromers.[9] While initially thought to be a receptorheterodimer, a review from 2015 determined that the A2A-DRD2 heteromer is aheterotetramer composed of A2A and DRD2 homodimers (i.e., two adenosine A2A receptors and two dopamine D2 receptors).[10] Maggio and co-workers showed in 1993 the ability of themuscarinic M3 receptor andα2C-adrenoceptor to heterodimerize.[11] The first direct evidence that GPCRs functioned as oligomersin vivo came from Overton and Blumer in 2000 by fluorescence resonance energy transfer (FRET) analysis of the α-factor receptor in the yeastSaccharomyces cerevisiae.[12] In 2005, further evidence was provided that receptor oligomerization plays a functional role in a living organism with regulatory implication.[13] The crystal structure of theCXCR4 dimer was published in 2010.[14]
GPCR oligomers consist of receptordimers,trimers,tetramers, and complexes of higher order. These oligomers are entities with properties that can differ from those of the monomers in several ways.[15] The functional character of a receptor is dependent on itstertiary orquaternary structure. Within the complex protomers act as allosteric modulators of another. This has consequences for:
^Fraser CM, Venter JC (November 1982). "The size of the mammalian lung beta 2-adrenergic receptor as determined by target size analysis and immunoaffinity chromatography".Biochem. Biophys. Res. Commun.109 (1):21–9.doi:10.1016/0006-291x(82)91560-1.PMID6297476.
