Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains. Underhill, S. M., Hullihen, P. D., Chen, J., Fenollar-Ferrer, C., Rizzo, M. A., Ingram, S. L., & Amara, S. G. Molecular Psychiatry, 26(4):1208–1223, April, 2021. Bandiera_abtest: a Cc_license_type: cc_by Cg_type: Nature Research Journals Number: 4 Primary_atype: Research Publisher: Nature Publishing Group Subject_term: Cell biology;Neuroscience Subject_term_id: cell-biology;neuroscience
Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains [link]Paper  doi  abstract   bibtex   
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.
@article{underhill_amphetamines_2021,
	title = {Amphetamines signal through intracellular {TAAR1} receptors coupled to {Gα13} and {GαS} in discrete subcellular domains},
	volume = {26},
	copyright = {2019 This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply},
	issn = {1476-5578},
	url = {https://www.nature.com/articles/s41380-019-0469-2},
	doi = {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.},
	language = {en},
	number = {4},
	urldate = {2021-12-27},
	journal = {Molecular Psychiatry},
	author = {Underhill, Suzanne M. and Hullihen, Patrick D. and Chen, Jingshan and Fenollar-Ferrer, Cristina and Rizzo, M. A. and Ingram, Susan L. and Amara, Susan G.},
	month = apr,
	year = {2021},
	note = {Bandiera\_abtest: a
Cc\_license\_type: cc\_by
Cg\_type: Nature Research Journals
Number: 4
Primary\_atype: Research
Publisher: Nature Publishing Group
Subject\_term: Cell biology;Neuroscience
Subject\_term\_id: cell-biology;neuroscience},
	keywords = {Cell biology, Neuroscience},
	pages = {1208--1223},
}

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