A GPCR oligomer is a protein complex that consists of a small number (ὀλίγοι oligoi "a few", μέρος méros "part, piece, component") of G protein-coupled receptors (GPCRs). It is held together by or by intermolecular forces. The Protein subunit within this complex are called protomers, 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 simplest homomeric GPCR oligomers.
Receptor heterodimers – which consist of two different GPCRs – are the simplest GPCR oligomers.
The existence of receptor is a general phenomenon, whose discovery has superseded the prevailing concept of the function of receptors as plain monomers, and has far-reaching implications for the understanding of neurobiological diseases as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.
Discovery
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 when
Robert Lefkowitz observed that β-adrenoceptors display negative binding
cooperativity.
At the beginning of the 1980s, it was hypothesized, receptors could form larger
protein complex, the so-called mosaic form,
where two receptors may interact directly with each other.
Mass determination of β-adrenoceptors (1982)
and muscarinic receptors (1983),
supported the existence of
homodimer or tetrameric complexes. In 1991, the phenomenon of receptor crosstalk was observed between adenosine A
2A (A2A) and dopamine D
2 receptor (DRD2) thus suggesting the formation of heteromers.
While initially thought to be a receptor
heterodimer, a review from 2015 determined that the A2A-DRD2 heteromer is a
heterotetramer composed of A2A and DRD2 homodimers (i.e., two adenosine A2A receptors and two dopamine D2 receptors).
Maggio and co-workers showed in 1993 the ability of the muscarinic M
3 receptor and α2C-adrenoceptor to heterodimerize.
The first direct evidence that GPCRs functioned as oligomers
in vivo came from Overton and Blumer in 2000 by fluorescence resonance energy transfer (FRET) analysis of the α-factor receptor in the yeast
Saccharomyces cerevisiae.
In 2005, further evidence was provided that receptor oligomerization plays a functional role in a living organism with regulatory implication.
The crystal structure of the CXCR4 dimer was published in 2010.
Consequences of oligomerization
GPCR oligomers consist of receptor
Protein dimer,
Protein trimer, tetramers, and complexes of higher order. These oligomers are entities with properties that can differ from those of the monomers in several ways.
The functional character of a receptor is dependent on its tertiary or quaternary structure. Within the complex protomers act as allosteric modulators of another. This has consequences for:
-
the supply of the cell surface with receptors
-
the ligand binding at corresponding
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the G-protein coupling
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the GPCR-mediated signal transduction
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modifying the desensitization profile
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the tendency for endocytosis and internalization
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the post-endocytotic fate of the receptors
Detection
There are various methods to detect and observe GPCR oligomers.
See also
Further reading
External links
