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. 2010 Mar;31(3):124-30.
doi: 10.1016/j.tips.2009.11.008. Epub 2010 Jan 7.

Receptor heteromerization and drug discovery

Raphael Rozenfeld  1 , Lakshmi A Devi
Affiliations

Receptor heteromerization and drug discovery

Raphael Rozenfeld et al. Trends Pharmacol Sci. 2010 Mar.

Abstract

G-protein-coupled receptors (GPCRs) are membrane proteins that convert extracellular information into intracellular signals. They are involved in many biological processes and therefore represent powerful targets to modulate physiological and pathological states. Recent studies have demonstrated that GPCR activity is regulated by several mechanisms. Among these, protein-protein interactions (and in particular interactions with other receptors leading to heteromerization) has been shown to have an important role in modulating GPCR function. This has expanded their repertoire of signaling and added a new level of regulation to their physiological roles. Emerging studies provide evidence for tissue-specific and disease-specific receptor heteromerization. This suggests that heteromers represent novel drug targets for the identification of selective compounds with potentially fewer side-effects.

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Figures

Figure 1
Figure 1. Modulation of receptor function by heteromerization (schematic)
(a) Heteromerization leads to the formation of an altered ligand binding site. Shown for DOR-KOR [15,37], DOR-MOR [14,17] and MOR-sst2A [54]. (b) Heteromerization leads to a decrease or increase in coupling to the G-protein. Decreased coupling was shown for the DOR-MOR heteromer [14]; increased coupling was shown for α2-AR-MOR [21], and AT1R-B2R [13]. (c) Heteromerization leads to coupling to a new G-protein. Shown for MOR-DOR heteromer coupling to Gαz [26,55]; heteromerization of two differently coupled receptors leads to preferential coupling to one G-protein upon co-stimulation. Shown for DOR-SNSR-4 [23]. (d) Heteromerization leads to a switch in receptor coupling, from G-protein to β-arrestin, and subsequent differential signaling and transcription factor activation. Shown for the MOR-DOR heteromer [28].
Figure 2
Figure 2. Emerging techniques to detect (a–c) and modulate (d–i) heteromers
GPCR heteromers can be detected using three main approaches. (a) Fluorophore-coupled ligand-mediated FRET. Fluorophore-coupled ligands for two receptors can be analyzed using FRET only if their two cognate receptors are in close proximity in a heteromeric complex. (b) Heteromer-selective antibodies that recognize only heteromers can be used to study the localization and levels of heteromers. (c) Heteromer-specific ligands can bind only to the altered receptor binding pocket formed in a heteromer. GPCR heteromers can be modulated using six main approaches. (d) Heteromer-specific agonists can activate a receptor only if in a heteromeric form. (e) Heteromer-specific antagonists can block a receptor only if in a heteromeric form. (f) Heteromer-specific antibodies can block receptor binding and/or signaling only if in a heteromeric form. (g) Activating heteromer-specific antibodies can activate receptors only if in a heteromeric form. (h) Bivalent ligands can bind and activate receptors only if their cognate receptors are in a heteromer. (i) The ligand of one receptor can act as a negative or positive allosteric modulator of the interacting receptor in a heteromer. The allosteric modulator can alter the binding and/or signaling properties of the interacting receptor.
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