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    Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

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    Author
    Underhill, S.M.
    Hullihen, P.D.
    Chen, J.
    Fenollar-Ferrer, C.
    Rizzo, M.A.
    Ingram, S.L.
    Amara, S.G.
    Date
    2019-08-09
    Journal
    Molecular Psychiatry
    Publisher
    Nature Publishing Group
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41380-019-0469-2
    Abstract
    The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
    Sponsors
    SGA and SMU were funded by the Intramural Research Program (ZIAMH002946).
    Keyword
    Amphetamines--pharmacology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/10390
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41380-019-0469-2
    Scopus Count
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