GPCR heteromers: An overview of their classification, function and physiological relevance

Abstract

G protein-coupled receptors (GPCRs) are capable of interacting to form higher order structures such as homomers and heteromers. Heteromerisation in particular has implications for receptor function, with research showing receptors can attain unique expression, ligand binding, signalling and intracellular trafficking upon heteromerisation. As such, GPCR heteromers represent novel drug targets with extensive therapeutic potential. Changes to ligand affinity, efficacy and G protein coupling have all been described, with alterations to these pharmacological aspects now well accepted as common traits for heteromeric complexes. Changes in internalisation and trafficking kinetics, as well as β-arrestin interactions are also becoming more apparent, however, few studies to date have explicitly looked at the implications these factors have upon the signalling profile of a heteromer. Development of ligands to target GPCR heteromers both experimentally and therapeutically has been mostly concentrated on bivalent ligands due to difficulties in identifying and developing heteromer-specific ligands. Improving our understanding of the pharmacology and physiology of GPCR heteromers will enable further development of heteromer-specific ligands with potential to provide therapeutics with increased efficacy and decreased side effects.

Fusarium graminearumSte3 G-Protein Coupled Receptor: A Mediator of Hyphal Chemotropism and Pathogenesis

“…Additionally, in that both receptors stimulate the CWI pathway, the interdependence could be consistent with a requirement for the formation of a peroxidase-stimulated heterodimer complex between Fg Ste2 and Fg Ste3 in the cell membrane. GPCR dimers (hetero and homo), as well as higher order oligomers, are well-documented to play important roles in modifying GPCR signal transduction ( 69 ), including a prior report of Ste2p homooligomerization in yeast mating ( 70 ).…”

Variation in responses to incretin therapy: Modifiable and non-modifiable factors

“…Multiple previous studies have shown that incretin receptors can form heterodimers, as demonstrated, for example, using bioluminescence resonance energy transfer (BRET) (Schelshorn et al, 2012;Whitaker et al, 2012;Dale et al, 2022). In particular (Roed et al, 2015), have shown that both the GIPR and the GCGR form heteromers with the GLP-1R when expressed in HEK-293 cells.…”

The chemokine receptor CCR5: multi-faceted hook for HIV-1

“…A Post-translational modifications (PMTs): sites of O-Glycosylation (Ser6, Thr16, Ser17) [ 70 , 71 ], sulfation (Tyr3, 10, 14, 15) [ 73 , 75 – 78 ], palmitoylation (Cys321, 323 and 324) [ 79 – 91 ] and phosphorylation (Ser336, 337, 342 and 349) [ 235 , 236 ] are represented by colored circles. Factors such as G-protein coupling ( B ) [ 28 , 60 , 97 – 103 ], mutations ( C ) [ 126 – 129 , 177 , 178 ], surface density [ 117 – 123 ] and oligomerization [ 136 – 149 ] ( D ) and membrane surrounding [ 152 – 173 ] ( E ) are also exemplified …”

“…Oligomerization of receptors —Many GPCRs are able to interact with each other to form higher-order structures (homomers and/or heteromers) (Fig. 2 D) that can, upon allosteric modulation, exhibit distinct biochemical properties from monomers [ 136 – 139 ]. Both CCR5 and CXCR4 have been shown to form many different homo and heteromers whose exhaustive lists can be found in [ 140 ] (Table 1) and [ 141 ] (Table 1).…”