Trends in Pharmacological Sciences
ReviewHeterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking
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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