alpha2C Adrenergic Receptors & Cutaneous Circulation

α2C 肾上腺素能受体

• 批准号: 7383892
• 负责人: NICHOLAS A FLAVAHAN
• 金额: $ 34.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383892
• 关键词: Adrenergic Receptor; Affect; Arteries; Blood Circulation; Blood flow; Cell surface; Cells; Closure; Constriction procedure; Cutaneous; Cyclic AMP; Data; Disease; Exposure to; GTP-Binding Proteins; Generations; Golgi Apparatus; Heat Losses; Human; Knockout Mice; Localized; Mediating; Mitochondria; Modeling; Mus; Norepinephrine; Oxidation-Reduction; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Physiological; Principal Investigator; RNA Interference; Raynaud Disease; Raynaud Phenomenon; Receptor Protein-Tyrosine Kinases; Regulation; Rho-associated kinase; Role; Serum; Signal Pathway; Signal Transduction; Skin; Tail; Transact; Transactivation; Tyrosine; Tyrosine Kinase Inhibitor; Vasospasm; chemotherapeutic agent; inhibitor/antagonist; novel; prevent; response; warm temperature

DESCRIPTION (provided by applicant): During cold exposure, cutaneous blood flow is reduced to prevent heat loss. This is mediated by increased sympathetic tone and a cold-induced sensitization of cutaneous arteries to constriction by norepinephrine. The latter effect is mediated by cold-induced amplification of (alpha2-adrenergic receptor (alpha2-AR) function. Although alpha2-ARs comprise 3 subtypes, only alpha2C-ARs respond to cold. Although alpha2C-ARs are not functional at 37 degrees C, they are entirely responsible for the cold-induced amplification of alpha2-AR constriction. At 37 degrees C, alpha2C-ARs are retained in the transGolgi network. Cooling causes alpha2C-AR translocation to the cell surface where they can respond to stimulation. The functional rescue of alpha2C-ARs is mediated by cold-induced activation of RhoA and rho kinase (ROCK). ROCKI inhibition by pharmacological blockade or RNA interference prevents cold-induced mobilization of alpha2C-ARs and cold-induced constriction in cutaneous arteries. We now demonstrate that cooling of tail arteries causes a rapid increase in ROS activity in VSM mitochondria, which precedes RhoA activation. Indeed, inhibition of ROS activity abolished cold-induced activation of RhoA and the functional rescue of alpha2C-ARs. The rescue of alpha2C-ARs was also reduced by a tyrosine kinase inhibitor. We propose that cold stimulates mitochondrial generation of ROS, causing transactivation of a receptor tyrosine kinase and activation of RhoA/ROCKI, enabling the spatial and functional rescue of alpha2C-ARs. We have also identified a novel cyclic AMP signaling pathway in cutaneous VSMs, which activates Rapl and causes profound increases in alpha2C-AR expression. We propose that these novel pathways for regulating the function and expression alpha2C-ARs may contribute to cold-induced vasospasm. Indeed, we present a new model of cold-induced vasospasm, generated by a chemotherapeutic agent that causes Raynaud's Disease in humans. This model displays a selective and dramatic increase in VSM alpha2C-AR activity, which precipitate vasospasm of cutaneous arteries. Three specific aims are proposed to pursue these novel and exciting findings and to investigate their physiological and pathophysiological significance.

描述（由申请人提供）：在寒冷暴露期间，皮肤血流量减少以防止热量损失。这是由交感神经张力增加和寒冷引起的皮肤动脉对去甲肾上腺素收缩的敏感性介导的。后一种效应是通过寒冷诱导的α2-肾上腺素能受体（α2-AR）功能放大介导的。尽管α2-AR包含3种亚型，但只有α2C-AR对寒冷有反应。尽管α2C-AR在37摄氏度下不起作用，它们完全负责冷诱导的 α2-AR 收缩放大。在 37 摄氏度时，α2C-AR 保留在反高尔基体中。冷却导致 alpha2C-AR 易位到细胞表面，在细胞表面，α2C-AR 的功能性拯救是通过药理学阻断或 RNA 干扰诱导的 RhoA 和 rho 激酶 (ROCK) 抑制介导的。防止冷诱导的 alpha2C-AR 动员和冷诱导的皮肤动脉收缩 我们现在证明，尾动脉冷却会导致 VSM 线粒体中 ROS 活性快速增加。事实上，ROS 活性的抑制消除了冷诱导的 RhoA 激活和 alpha2C-AR 的功能拯救。酪氨酸激酶抑制剂也减少了 α2C-AR 的拯救。我们认为寒冷会刺激线粒体产生 ROS，引起受体酪氨酸激酶的反式激活和 RhoA/ROCKI 的激活，从而实现 alpha2C-AR 的空间和功能拯救。我们还在皮肤 VSM 中发现了一种新的环 AMP 信号通路，该通路激活 Rapl 并导致 alpha2C-AR 表达显着增加。我们提出，这些调节 alpha2C-AR 功能和表达的新途径可能有助于寒冷诱导的血管痉挛。事实上，我们提出了一种由寒冷引起的血管痉挛的新模型，该模型是由导致人类雷诺氏病的化疗药物产生的。该模型显示 VSM α2C-AR 活性选择性显着增加，从而引发皮肤动脉血管痉挛。提出了三个具体目标来追求这些新颖且令人兴奋的发现并研究其生理和病理生理学意义。