Journal
PHARMACOLOGICAL REVIEWS
Volume 62, Issue 4, Pages 701-725Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/pr.110.002667
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Funding
- UK Medical Research Council [G0900050]
- Biotechnology and Biosciences Research Council [BB/E006302/1]
- National Health and Medical Research Council of Australia
- National Heart Foundation of Australia
- BBSRC [BB/E006302/1] Funding Source: UKRI
- MRC [G0900050] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E006302/1] Funding Source: researchfish
- Medical Research Council [G0900050] Funding Source: researchfish
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For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higherorder oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.
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