期刊
MOLECULAR PSYCHIATRY
卷 26, 期 4, 页码 1208-1223出版社
SPRINGERNATURE
DOI: 10.1038/s41380-019-0469-2
关键词
-
资金
- Intramural NIH HHS [ZIA MH002946] Funding Source: Medline
- NHLBI NIH HHS [R01 HL122827] Funding Source: Medline
- NIDDK NIH HHS [R01 DK077140] Funding Source: Medline
- NIH HHS [R21 OD018315] Funding Source: Medline
- NATIONAL INSTITUTE OF MENTAL HEALTH [ZIAMH002946] Funding Source: NIH RePORTER
This study demonstrates that the trace amine-associated receptor TAAR1 mediates the effects of amphetamines on dopamine neurons, providing insights into the mechanisms of action of amphetamines and related drugs. TAAR1 activates signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission, defining TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons.
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 G alpha signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G(13) and to G(S) alpha-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 G(13)-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据