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dc.contributor.authorUnderhill, S.M.
dc.contributor.authorRizzo, M.A.
dc.contributor.authorIngram, S.L.
dc.date.accessioned2019-08-26T14:44:27Z
dc.date.available2019-08-26T14:44:27Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85070340594&doi=10.1038%2fs41380-019-0469-2&partnerID=40&md5=9e4a86cd09df7f7ee2e9d9e2c30171f7
dc.identifier.urihttp://hdl.handle.net/10713/10390
dc.description.abstractThe 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.en_US
dc.description.sponsorshipSGA and SMU were funded by the Intramural Research Program (ZIAMH002946).en_US
dc.description.urihttps://doi.org/10.1038/s41380-019-0469-2en_US
dc.language.isoen-USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofMolecular Psychiatry
dc.subject.meshAmphetamines--pharmacologyen_US
dc.titleAmphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domainsen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41380-019-0469-2


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