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 (G_i and G_o). 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 G_i 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.

1. Center of Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, CPZN 8-218, Boston, Massachusetts 02114, USA.
2. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, CPZN 8-218, Boston, Massachusetts 02114, USA.
3. Rudolf-Virchow Center, DFG-Research Center for Experimental Biomedicine, University of Würzburg, Versbacher Strasse 9, 98078 Würzburg, Germany.
4. Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 98078 Würzburg, Germany.

Correspondence to: Jean-Pierre Vilardaga^1,2 e-mail: vilardaga.jeanpierre@mgh.harvard.edu

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