Review
Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking

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Abstract

Although classical models predict that G-protein-coupled receptors (GPCRs) function as monomers, several recent studies acknowledge that GPCRs exist as dimeric or oligomeric complexes. In addition to homodimers, heterodimers between members of the GPCR family (both closely and distantly related) have been reported. In some cases heterodimerization is required for efficient agonist binding and signaling, and in others heterodimerization appears to lead to the generation of novel binding sites. In this article, the techniques used to study GPCR heterodimers, and the ‘novel pharmacology’ and functional implications resulting from heterodimerization will be discussed.

Section snippets

Methods used to study GPCR dimers

A significant number of studies have suggested the presence of GPCR dimers 4, 5, 6. Because the results from these studies could also be explained by alternative interpretations, the existence of GPCR dimers and their pharmacological relevance remained obscure until recently. The availability of GPCR cDNAs facilitated studies to examine GPCR dimerization directly using biochemical, biophysical and functional complementation techniques.

Interactions between closely related members

The strongest evidence supporting an interaction between GPCRs that leads to modulation of receptor function has come from studies using the GABAB receptor, a member of GPCR family C (18, 19, 20, 21, 22). Efforts to clone the cDNA encoding the GABAB receptor resulted in the isolation of ‘GABAB(1a)’, which had a seven-TM topology. GABAB(1a) could not account for the functional activity of the native GABAB receptor. This led to an intense search and subsequent identification of a protein that

Interactions between distantly related members

The first set of studies to show an interaction between distantly related members of GPCR family A was reported by Rocheville and colleagues 15. These authors used a photobleaching FRET (pbFRET) technique to examine the ability of the sst5 receptor to interact with the dopamine D2 receptor, and showed that exposure to either a selective sst5 receptor agonist or a selective D2 receptor agonist resulted in an increase in the level of dimers, which suggests that activation of one of the receptors

Domains of the receptor involved in dimerization

An examination of the possible domains involved in GPCR interactions has implicated the extracellular, TM and/or C-terminal regions. The interaction could be mediated by covalent (disulfide) and/or non-covalent (ionic, hydrophobic) interactions of the N-terminal, TM and/or intracellular domains. Hydrophobic interactions within the TM domain are thought to provide the proper receptor conformation to facilitate the formation of additional interactions at other domains. An involvement of TM

Chemical name

SMS-(201–995)d-Phe-Cys-Phe=d-Tr-Lys-Thr-Cys-Thr-ol

Acknowledgements

I would like to thank Bryen Jordan and Ivone Gomes for critical reading of the manuscript and Clyde Scott for help with the illustrations. This work was supported in part by NIH grant K02 DA-00458.

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