MECHANISMS INVOLVED IN THE INTRACELLULAR RETENTION OF A2C ADRENERGIC RECEPTOR

A2C 肾上腺素受体细胞内保留所涉及的机制

• 批准号: 7720717
• 负责人: Catalin Filipeanu
• 金额: $ 11.3万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720717
• 关键词: Adrenergic Receptor; Arginine; Cell membrane; Cell surface; Computer Retrieval of Information on Scientific Projects Database; Endoplasmic Reticulum; Foundations; Funding; Golgi Apparatus; Grant; Guanosine Triphosphate Phosphohydrolases; Institution; Molecular; Numbers; Obstruction; RXR; Raynaud Phenomenon; Research; Research Personnel; Resources; Role; Sorting - Cell Movement; Source; Temperature; Therapeutic; United States National Institutes of Health; base; design; novel; receptor; research study; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent experimental evidence indicates an important role of alpha2C adrenergic receptor (AR) in Raynaud Phenomenon (RP). This receptor subtype is poorly expressed at the plasma membrane at 37oC, accumulating in endoplasmic reticulum (ER) and Golgi apparatus. Alpha2C-AR traffic to the cell surface is greatly enhanced after cold exposure. Structural analysis indicate that alpha2C-AR has an unusual high number of arginine (R) residues in the third intracellular loop and in the C-terminus, organized in eleven putative arginine sorting motifs (RXR). When embedded in other proteins, this RXR motif has been shown to induce ER retention. Our preliminary experiments demonstrated that deletion of the eight putative RXR motifs from the third intracellular loop greatly enhanced alpha2C-AR transport at 30oC. Based on this observation, our overall hypothesis is that unique structural motifs in alpha2C-AR regulate its trafficking. The experimental plan aims to distinguish between the contributions of ER arrest and obstruction of transport from Golgi to the plasma membrane and it will elucidate the mechanisms involved in the alpha2C traffic modulation by identifying the RXR motifs conferring temperature sensitivity to alpha2C-AR transport and determining the molecular mechanisms involved in these effects. Further, the role of Rab8 and Rab14 GTPases in the temperature sensitive alpha2C-AR receptor plasma membrane expression will be studied. These studies will produce novel and important information regarding the molecular determinants of alpha2C-AR intracellular accumulation and may provide foundation for designing more effective therapeutic strategies in Raynaud Phenomenon.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 最近的实验证据表明 α2C 肾上腺素受体 (AR) 在雷诺现象 (RP) 中发挥重要作用。该受体亚型在 37oC 时在质膜上表达较差，在内质网 (ER) 和高尔基体中积累。冷暴露后，Alpha2C-AR 到细胞表面的交通大大增强。结构分析表明，α2C-AR 在第三个细胞内环和 C 末端具有异常多的精氨酸 (R) 残基，组织成 11 个假定的精氨酸分选基序 (RXR)。当嵌入其他蛋白质中时，该 RXR 基序已被证明可诱导 ER 保留。我们的初步实验表明，从第三个细胞内环中删除八个假定的 RXR 基序大大增强了 30oC 下的 alpha2C-AR 转运。基于这一观察，我们的总体假设是 alpha2C-AR 中独特的结构基序调节其运输。该实验计划旨在区分 ER 阻滞和从高尔基体到质膜的运输受阻的贡献，并将通过识别赋予 alpha2C-AR 运输温度敏感性的 RXR 基序并确定参与这些效应的分子机制来阐明 alpha2C 运输调节所涉及的机制。此外，还将研究 Rab8 和 Rab14 GTPases 在温度敏感的 α2C-AR 受体质膜表达中的作用。这些研究将产生关于α2C-AR细胞内积累的分子决定因素的新颖且重要的信息，并可能为设计更有效的雷诺现象治疗策略提供基础。