Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster.
Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster.
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DOI：
10.1038/s41380-021-01275-y
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发表时间：
2021-12
影响因子：
11
通讯作者：
Melikian HE
中科院分区：
文献类型：
--
作者：
Fagan RR;Kearney PJ;Luethi D;Bolden NC;Sitte HH;Emery P;Melikian HE
多巴胺（DA）是运动、睡眠和奖励所必需的，DA信号传导受到突触前DA转运蛋白（DAT）的严格控制。治疗性和成瘾性精神兴奋剂，包括哌醋甲酯（利他林; MPH），可卡因和安非他明（AMPH），通过其竞争性DAT抑制剂（MPH，可卡因）和底物（AMPH）的作用显着提高细胞外DA。在小鼠和无脊椎动物中DAT沉默导致活动过度、睡眠减少和精神兴奋反应迟钝，突出了DAT在DA依赖性行为中的重要作用。DAT表面表达不是静态的，而是受内吞运输的动态调节。PKC刺激的DAT内吞作用需要神经元GT3、Rit 2，而小鼠DA神经元中Rit 2沉默影响精神兴奋剂敏感性。然而，目前尚不清楚Rit 2介导的精神兴奋剂敏感性的变化是否是DAT依赖性的。在这里，我们利用黑腹果蝇来测试果蝇Rit 2直系同源物Ric是否影响dDAT功能、贩运和DA依赖行为。与hDAT和Rit 2直接相关，dDAT和Ric直接相互作用，组成型活性Ric突变体Q117 L增加了细胞系和离体果蝇脑中dDAT的表面水平和功能。此外，DA能RicQ 117 L表达引起睡眠片段在DAT依赖性的方式，但总的睡眠和日常运动活动没有影响。重要的是，我们发现，Rit 2是必需的AMPH刺激的DAT内化在小鼠纹状体，DA能RicQ 117 L的表达显着增加果蝇AMPH敏感性的DAT依赖的方式，这表明一个保守的影响Ric-dependent DAT贩运AMPH敏感性。这些研究支持DAT/Rit 2相互作用可能通过调节DAT运输影响基线行为和AMPH敏感性。
Dopamine (DA) is required for movement, sleep, and reward, and DA signaling is tightly controlled by the presynaptic DA transporter (DAT). Therapeutic and addictive psychostimulants, including methylphenidate (Ritalin; MPH), cocaine, and amphetamine (AMPH), markedly elevate extracellular DA via their actions as competitive DAT inhibitors (MPH, cocaine) and substrates (AMPH). DAT silencing in mice and invertebrates results in hyperactivity, reduced sleep, and blunted psychostimulant responses, highlighting DAT’s essential role in DA-dependent behaviors. DAT surface expression is not static; rather it is dynamically regulated by endocytic trafficking. PKC-stimulated DAT endocytosis requires the neuronal GTPase, Rit2, and Rit2 silencing in mouse DA neurons impacts psychostimulant sensitivity. However, it is unknown whether or not Rit2-mediated changes in psychostimulant sensitivity are DAT-dependent. Here, we leveraged Drosophila melanogaster to test whether the Drosophila Rit2 ortholog, Ric, impacts dDAT function, trafficking, and DA-dependent behaviors. Orthologous to hDAT and Rit2, dDAT and Ric directly interact, and the constitutively active Ric mutant Q117L increased dDAT surface levels and function in cell lines and ex vivo Drosophila brains. Moreover, DAergic RicQ117L expression caused sleep fragmentation in a DAT-dependent manner but had no effect on total sleep and daily locomotor activity. Importantly, we found that Rit2 is required for AMPH-stimulated DAT internalization in mouse striatum, and that DAergic RicQ117L expression significantly increased Drosophila AMPH sensitivity in a DAT-dependent manner, suggesting a conserved impact of Ric-dependent DAT trafficking on AMPH sensitivity. These studies support that the DAT/Rit2 interaction impacts both baseline behaviors and AMPH sensitivity, potentially by regulating DAT trafficking.
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影响因子：
5.3
作者：
Gabriel, Luke R.;Wu, Sijia;Melikian, Haley E.
通讯作者：
Melikian, Haley E.
影响因子：
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作者：
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影响因子：
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Cartier, Etienne;Hamilton, Peter J.;Belovich, Andrea N.;Shekar, Aparna;Campbell, Nicholas G.;Saunders, Christine;Andreassen, Thorvald F.;Gether, Ulrik;Veenstra-Vanderweele, Jeremy;Sutcliffe, James S.;Ulery-Reynolds, Paula G.;Erreger, Kevin;Matthies, Heinrich J. G.;Galli, Aurelio
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Galli, Aurelio
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影响因子：
2.5
作者：
Cai W;Rudolph JL;Sengoku T;Andres DA
通讯作者：
Andres DA
影响因子：
4.3
作者：
Eissa N;Al-Houqani M;Sadeq A;Ojha SK;Sasse A;Sadek B
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