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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January 2011
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Review Article|
December 15 2010
Exploring a role for heteromerization in GPCR signalling specificity
Raphael Rozenfeld;
Raphael Rozenfeld
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
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Lakshmi A. Devi
Lakshmi A. Devi
1
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
1To whom correspondence should be addressed (email lakshmi.devi@mssm.edu).
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Publisher: Portland Press Ltd
Received:
March 29 2010
Revision Received:
August 09 2010
Accepted:
August 13 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 433 (1): 11–18.
Article history
Received:
March 29 2010
Revision Received:
August 09 2010
Accepted:
August 13 2010
Citation
Raphael Rozenfeld, Lakshmi A. Devi; Exploring a role for heteromerization in GPCR signalling specificity. Biochem J 1 January 2011; 433 (1): 11–18. doi: https://doi.org/10.1042/BJ20100458
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