Gpcr Dimerization

Current understanding of ligand-GPCR interactions was built upon a signaling unit consisting of one receptor protein and one effector, such as the het-erotrimeric G protein. However, from the birth of GPCRs as a receptor family, there were hints that these receptors might exist as multimers, of which the simplest case is a dimer [88] . Three advances in the past decade accelerated wider interest in GPCRs as dimeric proteins. First, the puzzle of inactive cloned GABAb receptors was solved by recognition that both GABABi and GABAB2 subunits were required for a functioning heterodimer [89, 90]. Later, atomic force microscopy revealed an elegant array of paired rhodopsin receptors in native rod outer segments [91] . albeit in membranes that contain the highest physiological concentration of any known GPCR. Finally, bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) techniques have been extensively applied to investigate the distance between individual GPCR monomers. Close apposition (<10 nm) between bioluminescent/fluorescent donor and acceptor-labeled proteins allows the donor energy to be transferred to the acceptor, resulting in increased longer wavelength emission. With some exceptions [92, 93], significant BRET/ FRET signals between a wide array of GPCR monomers support constitutive receptor homo- and heterodimerization in transfected cells [88, 94-96] . Such techniques support organized multimeric GPCR complexes but do not resolve whether dimerization is an essential prerequisite for ligand binding and signaling. Here, we consider the extent to which the protomers in a dimer must interact to activate downstream effectors, and whether communication between homo- and heterodimer ligand binding sites has the potential to generate novel pharmacology.

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