Dimerization and oligomerization of G protein-coupled receptors (GPCRs), proposed almost 30 years ago, have crucial relevance for drug design. Indeed, formation of GPCR oligomers may affect the diversity and performance by which extracellular signals are transferred to G proteins in
the process of receptor transduction. Thus, the control of oligomer assembly/disassembly and signaling will be a powerful pharmacological tool. This, however, requires (i) the determination that oligomerization takes place between particular receptors, (ii) the confirmation that the oligomer
has pharmacological importance and (iii) the availability of the oligomer 3D structure. This review aims at presenting experimental methods which unveil the complexity of GPCR dimerization/oligomerization focusing on biochemical and biophysical approaches. In total, we review 22 methods,
including biochemical methods (radiation inactivation technique, receptor co-expression and trans-complementation studies, cross-linking experiments, co-immunoprecipitation and immunoblotting studies and analysis of receptor mutants and chimeras) and biophysical methods (Fluorescence Resonance
Energy Transfer, (FRET), including photobleaching FRET (pb-FRET) and Time-Resolved FRET (TR-FRET), Luminescence Resonance Energy Transfer (LRET), Bioluminescence Resonance Energy Transfer (BRET), Bimolecular Fluorescence Complementation (BiFC), Luminescence Fluorescence Complementation (BiLC),
Fluorescence Recovery after Photobleaching (FRAP), Confocal Microscopy, Immunofluorescence Microscopy, Single Fluorescent-Molecule Imaging, Transmission Electron Microscopy, Immunoelectron Microscopy, Atomic Force Microscopy, Total Internal Reflectance Fluorescence Microscopy (TIRFM) and X-ray
Crystallography). For each method the scientific basis of the approach is shortly described followed by the extensive description of its application for studying GPCR oligomers presented according to their classes and families. Based on the wealth of experimental evidence, there is no
doubt about the existence of GPCR dimers, oligomers and receptor mosaics which constitute a new and highly promising group of novel drug targets for more selective and safer drugs.
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