Editorial overviewOligomerization of G-protein-coupled receptors: A reality
Section snippets
General concepts
G-protein-coupled receptors (GPCRs) have been classically perceived as receptors that do not ‘need’ to oligomerize to be functional, to execute their basic function of transducing a signal from ligand binding to G-protein activation (see Lohse, in this issue [1]). In fact, recent studies have shown that monomers of class A GPCRs (adrenergic β2, rhodopsin, and opioid μ receptors) reconstituted in lipid vesicles couple and activate their respective G proteins upon agonist binding [2, 3, 4]. Also
Investigation of receptor oligomerization by energy transfer-based techniques
The use of the energy transfer-based techniques bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) has been fundamental for taking the issue of GPCR oligomerization at the front of GPCR research, providing evidence for an increasing number of GPCR receptor heteromers in living cells. RET consists of a nonradioactive transfer of energy from a chromophore in an excited state, the ‘donor’, to a fluorescent ‘acceptor’ molecule. In FRET both molecules
Pharmacological implications of receptor oligomerization
Receptor heteromers, in particular, open up many implications for pharmacology, since they constitute new targets for drug development. An important step in this research field is the identification of receptor heteromers in native tissues. Thus, RET techniques are only straightforward when studying receptor heteromerization in artificial cell systems. Direct identification could be achieved by taking advantage of selective probes (for example, specific antibodies or labeled selective ligands)
Acknowledgements
Work supported by the intramural funds of the National Institute on Drug Abuse, NIH, DHHS and the Spanish Ministry of Education and Science (grant SAF2006-05481).
Sergi Ferré is a principal investigator at the National Institute on Drug Abuse, IRP, NIH, DHHS. He is also a guest professor from the Department of Biochemistry and Molecular Biology at the Faculty of Biology, University of Barcelona and adjunct associate professor from the Department of Pharmacology and Experimental Therapeutics at the University of Maryland School of Medicine. His general research interest is the understanding of the functional role of neurotransmitter receptor heteromers
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Sergi Ferré is a principal investigator at the National Institute on Drug Abuse, IRP, NIH, DHHS. He is also a guest professor from the Department of Biochemistry and Molecular Biology at the Faculty of Biology, University of Barcelona and adjunct associate professor from the Department of Pharmacology and Experimental Therapeutics at the University of Maryland School of Medicine. His general research interest is the understanding of the functional role of neurotransmitter receptor heteromers and their potential use as targets for drug development in neuropsychiatric disorders and drug addiction. He is particularly interested in the discovery of heteromers of receptors that are targets for addictive drugs (such as dopaminergic, cannabinoid, and nicotinic acethylcholine receptors) and with the analysis of their biochemical and pharmacological properties involving studies at the cellular level as well as at the in vivo level. At a more molecular level, he is also interested in finding the molecular determinants of the quaternary structure and function of receptor heteromers. He is principal editor of ‘TheScientificWorldJournal’ and member of the editorial board of ‘Central Nervous System Agents in Medicinal Chemistry’ and ‘Recent Patent Reviews on CNS Drug Discovery’.
Rafael Franco is a professor of Biochemistry and Molecular Biology. He has been a professor at the University of Barcelona, Spain, for 13 years. While keeping a link with this University he has recently moved to the Center for Applied Medical Research (http://www.cima.es), at the University of Navarra, Pamplona, Spain, where he heads the laboratory of Molecular Neurobiology and Neuropharmacology. His research interest focuses on the understanding of the physiological role of G-protein-coupled receptor heteromerization. He is particularly interested on the interactions established by adenosine, dopamine, and cannabinoid receptors in the striatum with emphasis in the relationships between quaternary structure of the heteromers and signaling and function. He has developed the framework of a dimer-based pharmacology based on the idea that drug development should contemplate G-protein-coupled receptor heteromers instead of monomers. He has helped in developing a dimer-based model, which is a more robust model than the ternary-complex model, to better understand G-protein-coupled receptor operation, improve data handling, and optimize drug discovery strategies. He serves on a number of grant review panels and consults for Pharmaceutical and Investment companies.