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首页> 外文期刊>Cellular Signalling >Interaction of the amyloid precursor like protein 1 with the alpha(2A)-adrenergic receptor increases agonist-mediated inhibition of adenylate cyclase
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Interaction of the amyloid precursor like protein 1 with the alpha(2A)-adrenergic receptor increases agonist-mediated inhibition of adenylate cyclase

机译：淀粉样蛋白前体样蛋白1与α（2A）-肾上腺素受体的相互作用增加了激动剂介导的腺苷酸环化酶抑制作用

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alpha(2)-adrenergic receptor agonists exert potent analgesic and sedative/hypnotic effects. In addition, they have been shown to be neuroprotective, but the mechanisms of these actions are still poorly defined. To isolate proteins that may control alpha(2)-adrenergic receptor function or trafficking, we performed a two-hybrid screen using the carboxy-terminal fourth intracellular tail of the alpha(2A)-adrenergic receptor as bait. This screen identified the amyloid precursor like protein 1 (APLP1), a homologue of the P-amyloid precursor protein involved in Alzheimer's disease, as alpha(2A)-adrenergic receptor-binding protein. GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha(2)-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha(2)-adrenergic receptors to the 13 amino acid residues Ser599-Ala611. Coimmunoprecipitations of transiently transfected cells with epitope-tagged APLP1 and alpha(2)-adrenergic receptors confirmed the interaction. Agonist treatment tended to increase the amount Of alpha(2A)-adrenergic receptor associated with APLP1 while coimmunoprecipitations were not affected by the state of receptor phosphorylation or cotransfection of arrestin-3. Confocal laser microscopy showed that APLP1 causes a considerable shift of the U2A-adrenergic receptor localization from plasma membrane to intracellular compartments. Furthermore, cotransfection of alpha(2A)-adrenergic receptor and APLP1 into HEK293 cells significantly increased norepinephrine mediated inhibition of adenylate cyclase activity. These results suggest a possible role of APLP1 in regulation Of alpha(2A)-adrenergic receptor trafficking. Moreover, we speculate that this interaction may present one mechanism by which alpha(2)-adrenergic receptor agonists exert their neuroprotective effects. (c) 2006 Elsevier Inc. All rights reserved.
机译：alpha（2）-肾上腺素受体激动剂发挥有效的止痛和镇静/催眠作用。另外，它们已经显示出对神经的保护作用，但是这些作用的机制仍然不清楚。为了分离可能控制α（2）-肾上腺素受体功能或运输的蛋白，我们使用α（2A）-肾上腺素受体的羧基末端第四细胞内尾巴作为诱饵进行了两次杂交筛选。此筛选确定淀粉样蛋白前体像蛋白1（APLP1），是参与阿尔茨海默氏病的P淀粉样蛋白前体蛋白的同系物，为alpha（2A）-肾上腺素受体结合蛋白。 GST亲和色谱显示，APLP1与所有三种人类α（2）-肾上腺素受体亚型特异性相互作用，缺失突变分析将参与与α（2）-肾上腺素受体结合的APLP1域限制在13个氨基酸残基Ser599-Ala611上。带有表位标记的APLP1和alpha（2）-肾上腺素能受体的瞬时转染细胞的共免疫沉淀证实了这种相互作用。激动剂治疗倾向于增加与APLP1相关的α（2A）-肾上腺素能受体的量，而共免疫沉淀不受制于膜蛋白或磷酸化抑制蛋白3的状态。共聚焦激光显微镜检查表明，APLP1引起U2A-肾上腺素受体定位从质膜到细胞内区室的显着变化。此外，α（2A）-肾上腺素受体和APLP1共转染HEK293细胞显着增加去甲肾上腺素介导的对腺苷酸环化酶活性的抑制。这些结果表明APLP1在调节alpha（2A）-肾上腺素受体运输中的可能作用。此外，我们推测这种相互作用可能提出一种机制，通过该机制，α（2）-肾上腺素能受体激动剂发挥其神经保护作用。 （c）2006 Elsevier Inc.保留所有权利。

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