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Annu Rev Pharmacol Toxicol. 2016;56:403-25. doi: 10.1146/annurev-pharmtox-011613-135952. Epub 2015 Oct 22.

G Protein-Coupled Receptor Heteromers.

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Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; email:
Biologie et Bioinformatique des Systèmes de Signalisation (BIOS) Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements; CNRS, UMR7247, F-37380 Nouzilly, France.
LE STUDIUM Loire Valley Institute for Advanced Studies, F-45000 Orleans, France.
Current address: Department of Frontier Life Sciences, Nagasaki University, Nagasaki City, Nagasaki Prefecture 852-8588, Japan.
Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia.
Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia.
Dimerix Bioscience Limited, Nedlands, Western Australia 6009, Australia.


G protein-coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets.


allosterism; biochemical fingerprint; bivalent ligands; dimerization; heterodimerization; oligomers; proximity-based assays

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