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Direct inhibition of G protein signaling by cross‐conformational switches between α 2A ‐adrenergic and μ‐opioid receptors
Author(s) -
Vilardaga JeanPierre,
Nikolaev Viacheslav,
Lorenz Kristina,
Ferrandon Sebastien,
Lohse Martin J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.908.8
Subject(s) - g protein coupled receptor , receptor , signal transduction , chemistry , inhibitory postsynaptic potential , g protein , microbiology and biotechnology , μ opioid receptor , opioid , biophysics , neuroscience , biochemistry , biology
Morphine, the powerful analgesic, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, exert major inhibitory effects on peripheral as well as brain neurons by activating distinct cell surface G protein‐coupled receptors (GPCRs), the μ‐opioid (MOR) and α 2A ‐adrenergic receptors (α 2A AR), respectively. Both receptors activate common signal transduction pathways mediated through the inhibitory G proteins (Gi and Go). Here we show that the MOR and α 2A AR communicate with each other through a cross‐conformational switch that permits direct inhibition of one receptor by the other with sub‐second kinetics. We discovered that morphine binding to the MOR triggers a conformational change in the NE‐occupied α 2A AR, which inhibits its signaling to Gi and downstream MAP kinase cascade. These data highlight a new mechanism in signal transduction at the cell surface whereby a heterodimer between different GPCRs mediated conformational changes that propagate from one receptor to the other and cause its inactivation.