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Nat Chem Biol. 2008 Feb;4(2):126-31. doi: 10.1038/nchembio.64. Epub 2008 Jan 13.

Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling.

Author information

1
Center of Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, CPZN 8-218, Boston, Massachusetts 02114, USA. vilardaga.jeanpierre@mgh.harvard.edu

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 mu-opioid receptor (MOR) and alpha2A-adrenergic receptor (alpha2A-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 alpha2A-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 alpha2A-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.

PMID:
18193048
DOI:
10.1038/nchembio.64
[Indexed for MEDLINE]

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