Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling.
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.
Vilardaga
Jean-Pierre
JP
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
Nikolaev
Viacheslav O
VO
Lorenz
Kristina
K
Ferrandon
Sébastien
S
Zhuang
Zhenjie
Z
Lohse
Martin J
MJ
D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D020239:Receptor Cross-Talk; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C547768:ADRA2A protein, human; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019204:GTP-Binding Proteins