Editors' ChoiceBiochemistry

Will Heteromeric G Protein-Coupled Receptors Confound Drug Development?

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Science's STKE  19 Dec 2006:
Vol. 2006, Issue 366, pp. tw426
DOI: 10.1126/stke.3662006tw426

Although the jury is still out, evidence is accumulating that heterotrimeric guanine nucleotide-binding protein-coupled receptors (GPCRs) may function as dimers or oligomers. Even though much of the evidence is from experiments in which the receptors are heterologously expressed in transfected cells, the findings merit attention because of their implications for drug discovery (GPCRs being a major focus of the efforts of the pharmaceutical industry). Ellis et al. provide evidence for interaction of two GPCRs, the human cannabinoid CB1 receptor and the receptor for orexins (peptides that stimulate eating). The orexin-1 receptor was localized primarily at the cell surface in transfected human embryonic kidney (HEK) 293 cells, but when cells were also transfected with the CB1 receptor, orexin-1 receptors localized intracellularly, as did CB1 receptors when transfected alone. Single-cell FRET (fluorescence resonance energy transfer) imaging in cells expressing appropriately tagged receptors showed that the receptors indicated the close apposition of the expressed receptors at intracellular sites. The key finding, though, was that specific antagonists of either the CB1 receptor or orexin A receptors could alter the response of the other receptor to its normal ligand. In cells expressing both receptors, treatment with the CB1 receptor agonist caused both receptors to relocalize to the cell surface but reduced the potency of orexin A to produce changes in activity of mitogen-activated protein (MAP) kinases. Similarly, treatment of cells expressing both receptors with an orexin receptor antagonist reduced the potency of a CB1 receptor agonist to regulate MAP kinase activity. The authors point out that if such receptor interactions exist in vivo, their properties may substantially influence the specificity of agents designed for therapeutic purposes. The effects described in the current paper provide a means for ligands that have no affinity for a particular receptor to still alter the signaling properties of that receptor by influencing the localization and signaling of heterodimeric receptors.

J. Ellis, J. D. Pediani, M. Canals, S. Milasta, G. Milligan, Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. J. Biol. Chem. 281, 38812-38824 (2006). [Abstract] [Full Text]

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