GPCR dimerisation

Abstract

The concept that GPCRs exist and potentially function as dimers and/or higher oligomers has progressed recently from hypothesis to being widely accepted. A range of techniques has contributed to this understanding, including co-immunoprecipitation and various forms of fluorescence and bioluminescence resonance energy transfer. Although co-immunoprecipitation studies indicate the capacity of a wide range of GPCRs to form hetero-dimers as well as homo-dimers, this approach is not well suited to examine selectivity of interactions. Both bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) have been applied to the detection of GPCR dimerisation in intact cells and BRET and FRET have been used to attempt to quantitate the fraction of GPCRs present as dimers. Following heterologous expression, a considerable fraction of many GPCRs is not fully processed and is trafficked to the proteasome or lysosome for destruction. A distinct limitation of both BRET and conventional FRET approaches is that both the energy donor and energy acceptor tags are inside the cell. Time-resolved FRET employing N-terminally epitope-tagged GPCRs has been used to allow detection only of dimers trafficked successfully to the cell surface. Reports indicating the appearance of distinct pharmacology and function following co-expression of two GPCRs are fascinating. Much remains to be examined, however, on the specificity and mechanisms of these interactions and to develop techniques to monitor the function only of hetero-dimers when the corresponding homo-dimers must also be present.

Transmembrane domain IV of the Gallus gallus VT[sub 2] vasotocin receptor is essential for forming a heterodimer with the corticotrophin releasing hormone receptor

“…[10][11][12][13][14][15][16] Both computational and experimental efforts have been made to understand the basis of protein-protein interaction in GPCR oligomerization. The GABA B R, β 2 AR, prostaglandin receptors, and dopamine receptors have all been shown to dimerize at some point in their lifespan.…”

“…[10][11][12][13][14][15][16] The γ-amino-butyric acid B receptor (GABA B R), β 2 AR, prostaglandin receptors, and dopamine receptors have all been shown to dimerize at some point in their lifespan. The functional roles of dimerization include proper packaging, transport, and signal transduction.…”

Ligand-Induced Partitioning of Human CXCR1 Chemokine Receptors with Lipid Raft Microenvironments Facilitates G-Protein-Dependent Signaling

“…How cells direct their path when encountering multiple chemoattractant signals is still unclear. One concept is that GPCRs, including chemokine receptors, exist and potentially function as dimers or oligomers (13,26,41). Such a mechanism of interaction between receptors may contribute to the ability of cells to integrate various directional signals from different attractants and thus migrate to the correct destination.…”

The supramolecular structure of the GPCR rhodopsin in solution and native disc membranes

“…Radiation inactivation studies pointed out the presence of oligomeric structures of GPCRs and G proteins [9]. A number of pharmacological and chemical methods were more recently employed to validate formation and function of oligomeric/dimeric forms of GPCRs, and insightful reviews were published [10][11][12][13][14][15][16][17]. These experimental results include direct functional and obligatory dimerization for the coupling and intracellular transport between two homologous subunits of γ-aminobutyric acid (GABA) receptors [18][19][20], dimeric structure of the extracellular domain of the metabotropic glutamate receptor, linked by a disulfide bridge [21], genetic and biochemical evidence of oligomerization of the α-factor receptor in yeast [22], Cys cross-linking indicating a symmetrical dimer interface in the dopamine D2 receptor [23], and identification of a pentameric complex between the dimeric leukotriene B4 receptor BLT1 and its G protein [24].…”