Article abstract
Nature Chemical Biology 4, 126 - 131 (2008)
Published online: 13 January 2008 | doi:10.1038/nchembio.64
Conformational cross-talk between 
2A-adrenergic and 
-opioid receptors controls cell signaling
Jean-Pierre Vilardaga1,2, Viacheslav O Nikolaev3,4, Kristina Lorenz3, Sébastien Ferrandon1,2, Zhenjie Zhuang1,2 & Martin J Lohse3,4
Abstract
Morphine, a powerful analgesic, and norepinephrine, the principal neurotransmitter of sympathetic nerves, exert major inhibitory effects on both peripheral and brain neurons by activating distinct cell-surface G protein–coupled receptors—the 
-opioid receptor (MOR) and 
2A-adrenergic receptor (2A-AR), respectively. These receptors, either singly or as a heterodimer, activate common signal transduction pathways mediated through the inhibitory G proteins (Gi and Go). Using fluorescence resonance energy transfer microscopy, we show that in the heterodimer, the MOR and 2A-AR communicate with each other through a cross-conformational switch that permits direct inhibition of one receptor by the other with subsecond kinetics. We discovered that morphine binding to the MOR triggers a conformational change in the norepinephrine-occupied 2A-AR that inhibits its signaling to Gi and the downstream MAP kinase cascade. These data highlight a new mechanism in signal transduction whereby a G protein–coupled receptor heterodimer mediates conformational changes that propagate from one receptor to the other and cause the second receptor's rapid inactivation.
- Center of Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, CPZN 8-218, Boston, Massachusetts 02114, USA.
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, CPZN 8-218, Boston, Massachusetts 02114, USA.
- Rudolf-Virchow Center, DFG-Research Center for Experimental Biomedicine, University of Würzburg, Versbacher Strasse 9, 98078 Würzburg, Germany.
- Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 98078 Würzburg, Germany.
Correspondence to: Jean-Pierre Vilardaga1,2 e-mail: vilardaga.jeanpierre@mgh.harvard.edu
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