%0 Journal Article %1 Vilardaga2008 %A Vilardaga, J. P. %A Nikolaev, V. O. %A Lorenz, K. %A Ferrandon, S. %A Zhuang, Z. %A Lohse, M. J. %D 2008 %J Nat Chem Biol %K *Receptor *Signal 1/metabolism 3/metabolism Cell Cross-Talk GTP-Binding Humans Kinase Line Mitogen-Activated Models, Molecular Opioid, Phosphorylation Protein Proteins/metabolism Quaternary Structure, Transduction alpha-2/*chemistry/genetics/*metabolism mu/*chemistry/genetics/*metabolism Receptor Adrenergic %N 2 %P 126-31 %T Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18193048 %V 4 %X 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.

@article{Vilardaga2008, 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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Vilardaga, J. P. and Nikolaev, V. O. and Lorenz, K. and Ferrandon, S. and Zhuang, Z. and Lohse, M. J.}, biburl = {https://www.bibsonomy.org/bibtex/2f99f121033cbcab0158c9c57ae4729b5/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {3c559d3e1c9c8a34d464bc21d08b2605}, intrahash = {f99f121033cbcab0158c9c57ae4729b5}, issn = {1552-4469 (Electronic)}, journal = {Nat Chem Biol}, keywords = {*Receptor *Signal 1/metabolism 3/metabolism Cell Cross-Talk GTP-Binding Humans Kinase Line Mitogen-Activated Models, Molecular Opioid, Phosphorylation Protein Proteins/metabolism Quaternary Structure, Transduction alpha-2/*chemistry/genetics/*metabolism mu/*chemistry/genetics/*metabolism Receptor Adrenergic}, month = Feb, note = {Vilardaga, Jean-Pierre Nikolaev, Viacheslav O Lorenz, Kristina Ferrandon, Sebastien Zhuang, Zhenjie Lohse, Martin J Research Support, Non-U.S. Gov't United States Nature chemical biology Nat Chem Biol. 2008 Feb;4(2):126-31. Epub 2008 Jan 13.}, number = 2, pages = {126-31}, shorttitle = {Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling}, timestamp = {2010-12-14T18:22:43.000+0100}, title = {Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18193048}, volume = 4, year = 2008 }