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Review
.2011 Jan 1;433(1):11-8.
doi: 10.1042/BJ20100458.

Exploring a role for heteromerization in GPCR signalling specificity

Affiliations
Review

Exploring a role for heteromerization in GPCR signalling specificity

Raphael Rozenfeld et al. Biochem J..

Abstract

The critical involvement of GPCRs (G-protein-coupled receptors) in nearly all physiological processes, and the presence of these receptors at the interface between the extracellular and the intracellular milieu, has positioned these receptors as pivotal therapeutic targets. Although a large number of drugs targeting GPCRs are currently available, significant efforts have been directed towards understanding receptor properties, with the goal of identifying and designing improved receptor ligands. Recent advances in GPCR pharmacology have demonstrated that different ligands binding to the same receptor can activate discrete sets of downstream effectors, a phenomenon known as 'ligand-directed signal specificity', which is currently being explored for drug development due to its potential therapeutic advantage. Emerging studies suggest that GPCR responses can also be modulated by contextual factors, such as interactions with other GPCRs. Association between different GPCR types leads to the formation of complexes, or GPCR heteromers, with distinct and unique signalling properties. Some of these heteromers activate discrete sets of signalling effectors upon activation by the same ligand, a phenomenon termed 'heteromer-directed signalling specificity'. This has been shown to be involved in the physiological role of receptors and, in some cases, in disease-specific dysregulation of a receptor effect. Hence targeting GPCR heteromers constitutes an emerging strategy to select receptor-specific responses and is likely to be useful in achieving specific beneficial therapeutic effects.

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Figures

Figure 1
Figure 1. Ligand-mediated signal specificity of MOR
Abundant literature has characterized differential effects of distinct MOR ligands on receptor responses, as summarized in this Figure. Binding of one class of agonists (such as etorphine and enkephalins) to MOR leads to translocation of the receptor to non-raft domains [33], GRK3-dependent desensitization [37] and recruitment of β-arrestin, with the initiation of receptor endocytosis [–29] and β-arrestin-mediated signalling [33]. In contrast, binding of another class of agonists (such as morphine) to MOR induces G-protein-mediated signalling and JNK-dependent desensitization [37], and does not lead to translocation to non-raft domains, β-arrestin recruitment or endocytosis [–29,32,33].
Figure 2
Figure 2. Examples of the alteration of receptor properties by heteromerization
Figure 3
Figure 3. Heteromer-mediated signal specificity: the case of the MOR homomers and MOR–DOR heteromers
Under normal physiological conditions, MOR is found mostly in the homomeric state. Morphine stimulation induces G-protein-mediated signalling and leads to analgesic effects. In contrast, upon chronic treatment with morphine the abundance of MOR–DOR heteromers increases [67]. MOR–DOR heteromers recruit β-arrestin, which alters MOR signalling [64]; this is thought to contribute to the impaired analgesic effect of morphine upon its chronic administration. Occupancy of the DOR-binding site allows for the restoration of MOR signalling and analgesic effects of morphine [54,64].
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