Excitements and challenges in GPCR oligomerization: molecular insight from FRET

G protein-coupled receptors (GPCRs) are the largest family of proteins involved in signal transduction across cell membranes, and they represent major drug targets in all clinical areas. Oligomerization of GPCRs and its implications in drug discovery constitute an exciting area in contemporary biology. In this Review, we have highlighted the application of fluorescence resonance energy transfer (FRET) in exploring GPCR oligomerization, with special emphasis on possible pitfalls and experimental complications involved. Based on FRET photophysics, we discuss some of the possible complications, and recommend that FRET results in complex cellular environments should be interpreted with caution. Although both hetero- and homo-FRET are used in measurements of GPCR oligomerization, we suggest that homo-FRET enjoys certain advantages over hetero-FRET. Given the seminal role of GPCRs as current drug targets, we envision that methodological progress in studying GPCR oligomerization would result in better therapeutic strategies.