G-protein-coupled receptors (GPCRs) are physiologically important transmembrane
proteins that sense signaling molecules such as hormones, neurotransmitters, and various
sensory stimuli; GPCRs represent major molecular targets for drug discovery. Although
GPCRs traditionally have been thought to function as monomers or homomers, in the recent
years these proteins have also been shown to function as heteromers. Heteromerization
among GPCRs is expected to generate potentially large functional and physiological diversity and to provide
new opportunities for drug discovery. However, due to the existence of numerous combinations, the larger
universe of possible GPCR heteromers is unknown, and thus its functional significance is still poorly understood.
The oligomerization of GPCRs in living cells now has been demonstrated in mammalian cells and in
native tissues by using genetic, biochemical, and physiological approaches, as well as various resonance energy
transfer (RET) technologies. In addition, the yeast Saccharomyces cerevisiae, which can serve as a biosensor
for monitoring eukaryotic biological processes, can also be used for the identification of functionally
significant heteromer pairs of GPCRs. In this review, we focus on studies of GPCR oligomers, and summarize
the technologies used to evaluate GPCR oligomerization. We additionally consider the potential limitations of
these methods at present, and envision the possible future applications of these techniques.
Keywords: G-protein-coupled receptors, oligomerization, resonance energy transfer, Saccharomyces cerevisiae,
two-hybrid system, reporter gene assay, drug discovery.
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