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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • GTP-Binding Proteins / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Molecular
  • Phosphorylation
  • Protein Structure, Quaternary
  • Receptor Cross-Talk*
  • Receptors, Adrenergic, alpha-2 / chemistry*
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction*


  • ADRA2A protein, human
  • Receptors, Adrenergic, alpha-2
  • Receptors, Opioid, mu
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins

Associated data

  • PubChem-Substance/46394454
  • PubChem-Substance/46394455
  • PubChem-Substance/46394456
  • PubChem-Substance/46394457