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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity
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Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity

机译：血清素转运蛋白和神经元一氧化氮合酶之间的物理相互作用是其活性相互调节的基础

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摘要

The spatiotemporal regulation of neurotransmitter transporters involves proteins that interact with their intracellular domains. Using a proteomic approach, we identified several proteins that interact with the C terminus of the serotonin transporter (SERT). These included neuronal nitric oxide synthase (nNOS), a PSD-95/Disc large/ZO-1 (PDZ) domain-containing protein recruited by the atypical PDZ binding motif of SERT. Coexpression of nNOS with SERT in HEK293 cells decreased SERT cell surface localization and 5-hydroxytryptamine (5-HT) uptake. These effects were absent in cells transfected with SERT mutated in its PDZ motif to prevent physical association with nNOS, and 5-HT uptake was unaffected by activation or inhibition of nNOS enzymatic activity. 5-HT uptake into brain synaptosomes was increased in both nNOS-deficient and wild-type mice i.v. injected with a membrane-permeant peptidyl mimetic of SERT C terminus, which disrupted interaction between SERT and nNOS, suggesting that nNOS reduces SERT activity in vivo. Furthermore, treating cultured mesencephalic neurons with the mimetic peptide similarly increased 5-HT uptake. Reciprocally, indicating that 5-HT uptake stimulates nNOS activity, NO production was enhanced on exposure of cells cotransfected with nNOS and SERT to 5-HT. This effect was abolished by 5-HT uptake inhibitors and absent in cells expressing SERT mutated in its PDZ motif. In conclusion, physical association between nNOS and SERT provides a molecular substrate for their reciprocal functional modulation. In addition to showing that nNOS controls cell surface localization of SERT, these findings provide evidence for regulation of cellular signaling (NO production) by a substrate-carrying transporter.
机译：神经递质转运蛋白的时空调节涉及与其细胞内结构域相互作用的蛋白质。使用蛋白质组学方法，我们鉴定了几种与血清素转运蛋白（SERT）C末端相互作用的蛋白质。这些包括神经元一氧化氮合酶（nNOS），一种通过SERT的非典型PDZ结合基序募集的PSD-95 / Disc large / ZO-1（PDZ）域蛋白。 nNOS与SERT在HEK293细胞中的共表达降低了SERT细胞表面定位和5-羟色胺（5-HT）摄取。这些效应在用PDZ基序突变的SERT转染的细胞中不存在，以防止与nNOS的物理缔合，并且5-HT摄取不受nNOS酶活性的激活或抑制的影响。在nNOS缺乏和野生型小鼠中，脑内突触体中5-HT的摄取均增加。注射了SERT C末端的膜透性肽基模拟物，该模拟物破坏了SERT与nNOS之间的相互作用，提示nNOS会降低体内的SERT活性。此外，用模拟肽处理培养的中脑神经元同样增加了5-HT的摄取。相应地，表明5-HT摄取刺激了nNOS活性，当用nNOS和SERT共转染的细胞暴露于5-HT时，NO的产生增加。这种作用已被5-HT吸收抑制剂取消，而在表达其PDZ基序中突变的SERT的细胞中则不存在。总之，nNOS和SERT之间的物理联系为它们的相互功能调节提供了分子底物。除了显示nNOS控制SERT的细胞表面定位外，这些发现还为通过底物转运蛋白调节细胞信号传导（NO产生）提供了证据。

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