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

基本信息

批准号：
8168192
负责人：
Catalin Filipeanu
金额：
$ 18.26万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8168192
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 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

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 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

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项目摘要

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.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。最近的实验证据表明，α2C肾上腺素能受体（AR）在Raynaud现象（RP）中的重要作用。该受体亚型在37oC处的质膜上表达不佳，积聚在内质网（ER）和高尔基体设备中。冷暴露后，α2C-AR的流量大大增强。结构分析表明，α2C-AR在第三个细胞内环和C-末端中具有异常数量的精氨酸（R）残基，在11个推定的精氨酸排序基序（RXR）中组织。当嵌入其他蛋白质中时，该RXR基序已被证明会诱导ER保留。我们的初步实验表明，第三个细胞内环的八个假定RXR基序的删除大大增强了30oC的alpha2c-ar的运输。基于这一观察结果，我们的总体假设是α2C-AR中的独特结构基序调节其贩运。该实验计划旨在区分急诊室的抑制和从高尔基膜到质膜的运输的贡献，并通过识别RXR对Alpha2C-AR传输的温度敏感性来阐明Alpha2c交通调节的机制，并确定涉及这些效应的alpha2c-arthement。此外，将研究RAB8和RAB14 GTPase在温度敏感的α2C-AR受体质膜表达中的作用。这些研究将产生有关α2C-AR细胞内积累的分子决定因素的新颖和重要信息，并可能为在Raynaud现象中设计更有效的治疗策略提供基础。